2022 Fleming autofagia

ll
Review
The different autophagy degradation
pathways and neurodegeneration
Angeleen Fleming,1,2,3,9 Mathieu Bourdenx,4,5,9 Motoki Fujimaki,1,2 Cansu Karabiyik,1,2 Gregory J. Krause,6,7
Ana Lopez,1,2,3 Adrián Martı́n-Segura,6,7 Claudia Puri,1,2 Aurora Scrivo,6,7 John Skidmore,8 Sung Min Son,1,2
Eleanna Stamatakou,1,2 Lidia Wrobel,1,2 Ye Zhu,1,2 Ana Maria Cuervo,6,7,* and David C. Rubinsztein1,2,*
1Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge
Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK

2UK Dementia Research Institute, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge
Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK

3Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK
4Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France
5CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France
6Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA
7Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA
8The ALBORADA Drug Discovery Institute, University of Cambridge, Island Research Building, Cambridge Biomedical Campus, Hills Road,
Cambridge CB2 0AH, UK

9These authors contributed equally
*Correspondence: [email protected] (A.M.C.), [email protected] (D.C.R.)

https://doi.org/10.1016/j.neuron.2022.01.017
SUMMARY
The term autophagy encompasses different pathways that route cytoplasmic material to lysosomes for
degradation and includes macroautophagy, chaperone-mediated autophagy, and microautophagy. Since
these pathways are crucial for degradation of aggregate-prone proteins and dysfunctional organelles such
as mitochondria, they help to maintain cellular homeostasis. As post-mitotic neurons cannot dilute unwanted
protein and organelle accumulation by cell division, the nervous system is particularly dependent on auto-
phagic pathways. This dependence may be a vulnerability as people age and these processes become
less effective in the brain. Here, we will review how the different autophagic pathways may protect against
neurodegeneration, giving examples of both polygenic and monogenic diseases. We have considered
how autophagy may have roles in normal CNS functions and the relationships between these degradative
pathways and different types of programmed cell death. Finally, we will provide an overview of recently
described strategies for upregulating autophagic pathways for therapeutic purposes.
OVERVIEW OF DIFFERENT AUTOPHAGY PATHWAYS The molecular components of macroautophagy were origi-
nally described in yeast, where genetic screens identified more
The term autophagy describes a set of mechanistically distinct than 40 ATG (autophagy-related) proteins, most of them with
processes that diverse cells use to deliver cytoplasmic contents mammalian orthologs, that regulate macroautophagy at its
to lysosomes for degradation that includes macroautophagy, different stages (Mizushima et al., 2011). A key event in the for-
chaperone-mediated autophagy (CMA), and microautophagy. mation of phagophores is the conjugation of members of the
In this review, we will briefly describe these pathways, how ubiquitin-like ATG8 family (Figure 1), including the LC3 and
they impact neurological functions in health and disease, and GABARAP (gamma-aminobutyric-acid-receptor-associated pro-
the current pharmacological efforts to boost autophagic activ- tein) subfamilies, to phosphatidylethanolamine in precursor
ities as therapeutic strategies in neurodegenerative diseases. membranes. This event occurs on RAB11A-positive recycling en-
dosomes in a wide range of cells, including primary neurons (Puri
Macroautophagy core pathway et al., 2018). Thereafter, the autophagosomes are closed by
The first morphologically distinct structure in macroautophagy is ESCRT machinery (Takahashi et al., 2018) then released in a
the cup-shaped, double-membraned phagophore, whose edges step mediated by DNM2 (Puri et al., 2020).
extend and fuse to become an autophagosome (Figure 1). Auto- It is likely that there is a lipid transfer to growing autophago-
phagosome biogenesis is complex and involves multiple proteins somes via the ATG2-WIPI4 complex (Maeda et al., 2019) and
and lipids from various membrane sources, including the endo- that some lipid remodeling occurs on nascent autophagosomes
plasmic reticulum (ER), ER/mitochondria contact sites (MAM), mediated by the scramblase function of ATG9 that assists mem-
ER exit sites, recycling endosomes, Golgi, and plasma membrane brane expansion (Matoba et al., 2020). Most of the cell biology
(Axe et al., 2008; Ge and Schekman, 2014; Puri et al., 2013). and biochemistry of mammalian autophagy has been studied in
Neuron 110, March 16, 2022 ª 2022 Elsevier Inc. 935

ll
Review
(legend on next page)
936 Neuron 110, March 16, 2022

ll
Review
fibroblasts and cancer cell lines. While the pathway conservation or GABARAP and cooperates with reticulon 3 (RTN3, RHD-con-
across species suggests that the core biology will be essentially taining protein) on the ER membrane to trigger the recruitment of
similar in all cells, there may be neuron- or glial-specific adaptions. the specific area of the ER that need to be degraded inside the
autophagosome (Grumati et al., 2017). Other ER-phagy recep-
Selective macroautophagy (mitophagy, ER-phagy, tors include cell-cycle progression gene 1 (CCPG1), Sec62,
pexophagy, and aggrephagy) Atlastin-3 (ATL3), and testis-expressed 264 (TEX264) (Chino
Macroautophagy degrades long-lived, aggregate-prone pro- et al., 2019; Fumagalli et al., 2016). The existence of multiple re-
teins, protein complexes, and dysfunctional or damaged organ- ceptors suggests a redundancy or selectivity for types of ER.
elles. Substrate degradation can be facilitated by machinery that FAM134B and RTN3L are involved in starvation-induced ER-
enables their preferential sequestration via adapter proteins that phagy, while CCPG1 is induced during ER stress and Sec62
bridge components of the substrate (generally surface proteins participates in the recovery of ER stress (recovER-phagy). Muta-
which are ubiquitinated) and elements of the nascent autopha- tions in FAM134B and ATL3 have been linked to peripheral neu-
gosome, typically LC3 (Figure 1). These forms of selective ropathy, but the other ER-receptors have not been studied yet in
autophagy include mitophagy (mitochondria), pexophagy (per- the nervous system.
oxisomes), ribophagy (ribosomes), ER-phagy (ER), and aggreph-
agy (aggregate-prone proteins), among others. Pexophagy
Damaged or excess peroxisomes are degraded through auto-
Mitophagy phagy via pexophagy, where ubiquitination of PEX3 or PMP34
Mitophagy exists in several forms, depending on the mechanism on the cytosolic face of peroxisomes enables recognition by
of recruitment of the phagophore membrane to mitochondria. autophagy adapters P62 or NBR1, which target peroxisomes
The most well-studied form relies on the phosphatidylinositol- for autophagic degradation (Jo et al., 2020).
3,4,5-trisphosphate 3-phosphatase (PTEN)-induced putative ki-
nase 1 (PINK1) and the ubiquitin ligase Parkin. After mitochon- Aggrephagy
drial damage, PINK1 levels, which are normally low, increase, Most neurodegenerative diseases manifest with the accumula-
and PINK1 auto-phosphorylates to recruit cytosolic Parkin to tion of aggregates in vulnerable cell populations in the brain. Se-
the mitochondrial membrane, triggering mitophagy (Matsuda, lective degradation of protein aggregates is called aggrephagy.
2016). In PINK1-Parkin-dependent mitophagy, autophagy re- Misfolded, aggregate-prone proteins are ubiquitinated, recog-
ceptors such as optineurin (OPTN), nuclear domain 10 protein nized, and linked to the autophagy machinery by adapters
52 (NDP52) and trans-activating transcriptional regulatory pro- such as P62, NBR1, Tollip (Cue5 in yeast), OPTN (Shen et al.,
tein of HTLV-1 (TAX1)-binding protein 1 (TAX1BP1) recruit the 2017), and TAX1BP1 (Sarraf et al., 2020).
autophagosome biogenesis machinery to mitochondria (Geisler
et al., 2010; Narendra et al., 2010). Neuronal PINK1 or Parkin Lysophagy
deletions in mice cause only mild phenotypes, highlighting Damaged lysosomes are degraded by selective autophagy via
the existence of alternative mitophagy processes, including lysophagy, which protects cells from lysosomal cell death. Ly-
receptor-mediated (NIX/BNIP3L), ubiquitin-mediated (MUL1- sophagy appears to be ubiquitination-dependent and involves
dependent), and lipid-mediated (through exposure of the inner various canonical autophagy receptors, such as TAX1BP1
membrane mitochondrial lipid cardiolipin) pathways (Evans (Eapen et al., 2021) and TBK1 (Eapen et al., 2021), a protein
and Holzbaur, 2020). mutated in various diseases, including forms of amyotrophic
lateral sclerosis (ALS).
ER-phagy (reticulophagy)
Constitutive ER turnover is required to maintain proper cellular Major regulators
function. Autophagy contributes to ER remodeling via ER-phagy Macroautophagy can be stimulated by stresses including
or reticulophagy. The ER-phagy adapter FAM134B (family with nutrient depletion, growth factor deprivation, oxidative stress,
sequence similarity 134, member B), interacts directly with LC3 and protein aggregation (Menzies et al., 2017). Nutrient
Figure 1. Schematic representation of macroautophagy

Cell components to be degraded are engulfed in a double-membraned structure called the phagophore, the edges of which elongate and close to form auto-
phagosomes. These ultimately fuse with the lysosomal membrane for cargo degradation.
(A) Early steps in macroautophagy involve 2 ubiquitin-like conjugation cascades. Conjugation I leads to the formation of the Atg5-Atg12 conjugate mediated by
ATG7 (E1-like) and ATG10 (E2-like). This then forms a complex with ATG16L1. During Conjugation II, ATG4 cleaves the C terminus of LC3 generating LC3-I whose
C-terminal glycine can be conjugated to phosphatidylethanolamine (PE) by ATG7 (E1-like), ATG3 (E2-like), and ATG5-ATG12/ATG16L1 (E3-like) (generating
lipidated LC3 [LC3-II]). The other ATG8 family members (GABARAPs) use the same machinery to enable their conjugation to PE as LC3 proteins. The sites of LC3
conjugation to membranes are determined by the ATG5-ATG12-ATG16L1 complex, which localizes to the surface of the forming phagophore by interacting with
WIPI2. WIPI2 is recruited to these membranes by binding both to phosphatidylinositol 3-phosphate (PI3P) and RAB11A.
(B) During autophagosome formation, the phagophore double membrane elongates and fuses to form a double-membraned vesicle termed the autophagosome.
Cargo within autophagosomes can be trapped in a (1) bulk or (2) selective manner by autophagy cargo receptors, such as P62, leading to the selective autophagy
of specific substrates. Completion of vesicle closure to engulf regions of cytoplasm and organelles or to engulf specific cargoes such as aggregates
(aggrephagy), mitochondria (mitophagy), or ribosomes (ribophagy) is followed by release from the recycling endosome-RAB11A platform to which the LC3
conjugates. Finally, the autophagosome outer membrane fuses with the lysosomal membrane and cargo is released for complete degradation in the lyso-
somal lumen.
Neuron 110, March 16, 2022 937

ll
Review
starvation inhibits mechanistic target of rapamycin complex 1 protein systems ATG5-ATG12, ATG7-ATG8, ATG16, and
(mTORC1), a highly conserved negative regulator of autophagy ATG9, but requires ULK1 and PI3K-Beclin 1-VPS34 complexes
(Saxton and Sabatini, 2017). In nutrient-rich conditions, (Nishida et al., 2009). ATG5-ATG7-independent autophago-
mTORC1 interacts and phosphorylates ULK1 to inhibit auto- somes originate from the trans-Golgi membrane in a RAB9-
phagy. Upon starvation, mTORC1 sites on ULK1 are dephos- dependent manner (Honda et al., 2020). Non-canonical macro-
phorylated and ULK1 dissociates from mTORC1, thereby acti- autophagy has been shown to contribute to mitochondrial
vating ULK1 kinase activity (Hosokawa et al., 2009). In clearance during erythroid maturation or iPSC cell differentiation
mammals, mTORC1 activity is stimulated by growth factors and to the degradation of proinsulin granules in glucose-
through inhibition of the tuberous sclerosis complex (TSC) 1 deprived b cells (Honda et al., 2020). Neuronal non-canonical
and 2 (Dibble and Manning, 2013). Amino acids signal to autophagy is required for the degradation of ceruloplasmin to
mTORC1 through Rag GTPases independently of the TSC com- prevent iron deposition (Yamaguchi et al., 2020).
plex (Sancak et al., 2008). Recently, leucine was shown to signal
to mTORC1 in most cells, including neurons and glia, via its Chaperone-mediated autophagy
metabolite acetyl-coenzyme A (Ac-CoA), which stimulates acet- In CMA, substrate proteins are translocated across the lyso-
ylation of raptor and subsequent activation of mTORC1 and inhi- somal membrane, where they are targeted following the recogni-
bition of autophagy (Son et al., 2020). Autophagy can also be tion of a KFERQ-like targeting motif in their sequences by the
induced by low cellular energy levels/low glucose (increased heat shock cognate 71-kDa protein (HSC70) (Figure 2). The
AMP/ATP) sensed by AMP-activated protein kinase (AMPK). In HSC70/substrate complex binds the cytosolic tail of the lyso-
glucose-deprived cells, AMPK activates ULK1, which then phos- some-associated membrane protein type 2A (LAMP-2A) (Cuervo
phorylates and activates the lipid kinase PIKfyve (FYVE finger- and Dice, 1996), triggering its multimerization into a translocation
containing phosphoinositide kinase), thereby increasing synthe- complex. After unfolding, the substrate is internalized into the
sis of the phosphatidylinositol 5-phosphate PI(5)P (Karabiyik lysosomal lumen assisted by a lysosome resident HSC70, and
et al., 2021). PI(5)P upregulates autophagosome synthesis and the LAMP-2A complex is disassembled (Kaushik and Cuervo,
induces autophagic flux in the absence of PI(3)P in a VPS34-in- 2018). LAMP-2A levels and its assembly/disassembly in the
dependent manner (Vicinanza et al., 2015). Another key regulator lysosomal membrane are rate limiting for CMA.
of autophagy and lysosomal biogenesis is transcription factor EB HSC70 is the only chaperone required for CMA cargo recogni-
(TFEB) (Settembre et al., 2013). tion (Chiang et al., 1989), while HSP90, HSP40, the HSP70-
HSP90-organizing protein (Hop), the HSP70-interacting protein
Non-autophagic role of the ATG protein conjugation (Hip), and the BCL2-associated athanogene-1 protein (BAG-1),
system facilitate substrate unfolding, enhance substrate/LAMP2A bind-
Some ATGs have autophagy-independent functions. In LC3- ing and stabilize LAMP2A during its multimerization (Kaushik and
associated phagocytosis (LAP), ATGs contribute to immune regu- Cuervo, 2018). In all cell types studied to date, LAMP2A translo-
lation and inflammatory responses, particularly in phagocytic cation complex stability is regulated by the monomeric form of
cells. In LAP, LC3 is conjugated to phagosome single membranes the intermediate filament protein glial fibrillary acidic protein
(LAPosomes) that directly fuse to lysosomes (Galluzzi and Green, (GFAP) and the elongation factor-1 a (EF1a) in a GTP-dependent
2019). LAP is independent of the ULK1/FIP200/ATG13/ATG101 manner (Bandyopadhyay et al., 2010), and by lysosomal AKT
macroautophagy complex and is unresponsive to starvation or (Arias et al., 2015). Phosphorylation of lysosomal membrane
intracellular stress (Heckmann et al., 2017). Toll-like receptors AKT by mTORC2 is inhibitory for CMA, whereas its dephosphor-
(TLRs) and immunoglobulin (Ig) receptors participate in cargo ylation by the PHLPP1 kinase-phosphatase that binds to lyso-
recognition to activate LAP. The recognition of opsonized foreign somes in a Rac-1-dependent manner leads to maximal CMA
particles leads to the recruitment of LAP regulatory machinery to activation (Arias et al., 2015). The CMA target of AKT is GFAP,
the phagosome and the engulfed substrates are degraded also recently shown to be phosphorylated by class I PI3K with
following fusion with lysosomes (Heckmann et al., 2019). a similar inhibitory effect on CMA (Endicott et al., 2020). CMA
LC3 can also be conjugated to RAB5-, clathrin-positive endo- is also transcriptionally upregulated by NFAT, NRF2 and
somes that contain amyloid-b. This new function, called LANDO TPD52, whereas signaling through retinoic acid receptor alpha
(LC3-associated endocytosis), requires ATGs, such as LC3, (RARa) and growth hormone signaling transcriptionally repress
Rubicon and ATG5, but not FIP200. LANDO was described in mi- CMA (Anguiano et al., 2013).
croglia, where it enables removal of amyloid-b and ameliorates The KFERQ-like motif is necessary and sufficient for CMA tar-
pathology in a murine model of Alzheimer disease (AD) (Heck- geting, but because binding to HSC70 is dependent on the
mann et al., 2019). chemical properties of the motif (i.e., charge and polarity)
(Kaushik and Cuervo, 2018), multiple amino acid combinations
Non-canonical macroautophagy can build a functional (canonical) KFERQ-like motif. Post-trans-
Macroautophagy-like processes can also occur in the absence lational modifications (PTMs), such as phosphorylation or acety-
of some key ATG proteins, in what is called non-canonical mac- lation (Figure 2), can also generate functional motifs (by adding
roautophagy. Some cell types lacking Atg5 or Atg7, essential for the missing charges) or disrupt a motif (i.e., through ubiquitina-
canonical macroautophagy, still perform macroautophagy in tion of the residue’s lysine). Around 46% of the proteome con-
response to specific stressors (Nishida et al., 2009). Autophago- tains canonical motifs and an additional 30% can be generated
some formation in this case is independent of the ubiquitin-like via PTMs (Kirchner et al., 2019), but CMA degradation of those
938 Neuron 110, March 16, 2022

ll
Review
Figure 2. Schematic representation of chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI)
The first steps for cargo recognition are shared by CMA and eMI and are mediated by the binding of HSC70 to a targeting motif in the protein sequence bio-
chemically related to the pentapeptide KFERQ. The inset (top right) highlights the chemical requirements for KFERQ motifs and the PTMs such as phosphor-
ylation or acetylation that can generate motifs by providing the missing charges. This motif is necessary and sufficient for CMA, whereas it is necessary but
insufficient for eMI. Additional, as yet unknown, mediators are required for eMI targeting. HSC70 binds to the surface of late endosomes via phosphoserine and
triggers assembly of the ESCRT machinery for internalization of substrate into intraluminal vesicles. In CMA, binding of the HSC70/substrate complex to LAMP2A
at the lysosomal membrane triggers its multimerization to form a translocation complex that mediates the internalization of the substrate protein into the lumen for
degradation. LAMP2A is actively disassembled from the complex to initiate a new cycle of binding/internalization. LAMP2A also mobilizes laterally to incorporate
into lipid microdomains for its own degradation triggered by cathepsin A (CTSA). Phosph. gen., phosphorylation generated; Acetyl. Gen., acetylation generated.
proteins only occurs when their motif becomes accessible to the to phosphatidylserine in LE/MVB membranes (Morozova et al.,
chaperone (i.e., by protein conformational changes or dissocia- 2016), triggering substrate internalization into the lumen via
tion of protein-protein interactions). membrane invaginations that form in an ESCRT-dependent
manner. Cargo degradation protein can occur in the LE/MVB
Microautophagy and endosomal microautophagy compartment itself, although the bulk of degradation occurs af-
Microautophagy involves lysosomal degradation of cellular com- ter LE/MVB-lysosome fusion. An additional type of mammalian
ponents via membrane invaginations in compartments of the en- eMI, independent of HSC70 but dependent on some of the
dolysosomal system (Figure 3). Beside proteins, microautophagy ESCRT proteins involved in eMI, has been identified as part of
can also degrade organelles in yeast such as mitochondria, lipid the early response to amino acid starvation (Mejlvang et al.,
droplets, ER, peroxisomes, and even nuclear fragments (Schuck, 2018). This pathway degrades several macroautophagy recep-
2020); although thus far, only micro-ER-phagy has been identified tors, possibly regulating the switch between selective and in
in mammalian systems (Loi et al., 2019). bulk macroautophagy.
Mammalian microautophagy pathways all target their cargo to Little is known about the regulation and functional implications
late endosomes/multivesicular bodies (LE/MVBs) (Krause and of eMI in mammals. In Drosophila, eMI is upregulated in
Cuervo, 2021). The term endosomal microautophagy (eMI) refers response to oxidative and genotoxic stress (Mesquita et al.,
to the degradation of cytosolic proteins in LE/MVBs and can be 2020) and to nutrient deprivation (Jacomin et al., 2021; Mukher-
further sub-classified based on the selectivity of the cargo and jee et al., 2016). Basal eMI has been shown to contribute to local
the molecular machinery involved. The first type of eMI identified turnover of proteins in Drosophila neuromuscular junction synap-
requires, as in CMA, recognition of a KFERQ-like motif by HSC70 ses, and its blockage leads to impaired neurotransmission (Uyt-
(Figure 2) (Kirchner et al., 2019; Sahu et al., 2011). HSC70 binds terhoeven et al., 2015).
Neuron 110, March 16, 2022 939

ll
Review
Figure 3. Schematic representation of
microautophagy
Bulk of proteins and cells components such as or-
ganelles in bulk (1) can be integrated into lysosomes
and late endosomes directly through invaginations
at the lysosomal membrane. Cytosolic proteins
targeted by Hsc70 can be also selectively degraded
by its internalization into late endosome in-
vaginations in a process known as endosomal mi-
croautophagy (2).
Different types of autophagy, although

not redundant, are capable of compen-
sating for each other. Early studies revealed
that mouse fibroblasts with defective mac-
roautophagy displayed elevated constitu-
tive CMA activity. Compensatory activation
of macroautophagy and the UPS occurs in a
variety of non-neuronal tissues in CMA-defi-
cient mouse models (mouse fibroblasts,
liver, T cells) (Kaushik and Cuervo, 2018).
However, this compensation is not universal
as it was not observed, for example, in
the retina or in hematopoietic stem cells
(Dong et al., 2021; Rodrı́guez-Muela et al.,
2013). Likewise, compensatory activation
of macroautophagy was not observed
in CMA-defective neurons, leading to
an early phenotype of proteostasis
failure (already evident at 6 months)
Autophagic crosstalk (Bourdenx et al., 2021). In fact, a direct comparison of insoluble
The ubiquitin-proteasome system (UPS), mostly responsible for fractions isolated from the brains of CMA- (Lamp2A/) and mac-
degradation of soluble and short-lived proteins, shares some key roautophagy-deficient (Atg7/) mice highlighted that these
players with autophagy, like ubiquitin. This small protein can two pathways handle different portions of the proteome in
modulate the degradation rates of proteins or organelles through neurons (only 50% of the aggregated proteins were similar).
the UPS or macroautophagy (Komander and Rape, 2012). More- Understanding the mechanisms behind reciprocal macroautoph-
over, ubiquitination of the core macroautophagic machinery agy and CMA compensation in non-neuronal cells could
serves as an important regulatory mechanism (reviewed in Yin identify novel therapeutic targets to upregulate these pathways
et al., 2020). The macroautophagy receptor, P62, has also in neurons in neurodegenerative conditions.
been reported to escort ubiquitinated proteins for proteasomal
degradation (Seibenhener et al., 2004), depending on its oligo- Roles of autophagic pathways in the healthy nervous
merization state (Lu et al., 2017). system
Accumulating evidence suggests a compensatory balance Maintaining neuronal function
between these two degradation pathways, whereby UPS inhibi- Neurons are post-mitotic, long-lived cells that require robust
tion upregulates macroautophagic proteins by mechanisms still protein and organelle quality control mechanisms. Neuronal
not fully understood (reviewed in Sun-Wang et al., 2020). Protea- loss of ATGs results in accumulation of ubiquitin-positive protein
some inhibition enhances nuclear translocation of TFEB (Li et al., aggregates, axonal swellings, and neuronal degeneration,
2019a), and other transcription factors that induce autophagy, demonstrating that basal macroautophagy is critically important
like Nrf1 and Nrf2 (nuclear factor erythroid-2-like 1 and 2) (Pa- for neuronal health (Menzies et al., 2017). Similarly, loss of the
jares et al., 2016; Sha et al., 2018). The proteasome itself can CMA receptor LAMP2A disrupts neuronal proteostasis and func-
be a substrate of macroautophagy under stress conditions in tion (Bourdenx et al., 2021). While impaired macroautophagy
the process called proteaphagy (Cohen-Kaplan et al., 2016; and CMA accelerate the accumulation of aggregate-prone
Cuervo et al., 1995). Although macroautophagy-deficient cells proteins (a hallmark of most neurodegenerative diseases), they
appear to accumulate proteasomes due to decreased proteaph- likely protect neuronal health via several additional mechanisms.
agy and increased expression of the proteasome subunits Neurons need to maintain a healthy pool of mitochondria, as
(Wang et al., 2013), degradation of proteasome substrates they have high energy demands. The strong genetic connection
seems to be compromised in these cells, without changes in pro- between mitophagy and neurodegeneration emphasizes the
teasome activity (Korolchuk et al., 2009). importance of this pathway in neurons. However, the role of
940 Neuron 110, March 16, 2022

ll
Review
neuronal mitophagy in non-pathological conditions is unclear. macroautophagy induction to enhance activity-dependent plas-
Mice deficient for proteins involved in selective mitophagy, ticity changes in hippocampal neurons after chemical long-term
such as P62, PINK1, and Parkin, do not show accumulation of potentiation (LTP) (Glatigny et al., 2019). Similarly, mice deficient
defective mitochondria or neuronal loss (Martinez-Vicente, in neuronal WIPI4 show attenuated hippocampal LTP (Zhao
2017). In contrast, PINK1-knockout rats or PINK1/Parkin-defi- et al., 2015). In contrast, suppression of macroautophagy is
cient flies display mitochondrial abnormalities and neurodegen- required for BDNF-induced LTP (Nikoletopoulou et al., 2017).
eration (Martinez-Vicente, 2017). The mitochondrial defects in During long-term depression, endocytic sorting and autophagy
the PINK1/Parkin-depleted models may be independent of mi- induction regulate the degradation of AMPA receptors (Ehlers,
tophagy. For example, PARIS (ZNF746), a substrate of PINK1- 2000; Shehata et al., 2012). Further studies are required to un-
mediated phosphorylation and Parkin-mediated ubiquitination, derstand how macroautophagy regulates synaptic strength.
accumulates following Parkin deletion and leads to repression CMA plays an important role in maintenance of the neuronal
of the peroxisome-proliferator-activated receptor gamma proteome with higher propensity for aggregation. Acute
coactivator 1a (PGC-1a), a master coregulator of mitochondrial silencing of LAMP2A in dopaminergic neurons leads to the accu-
function, biogenesis, and mitochondrial oxidative stress man- mulation of a-synuclein and ubiquitinated proteins, neurodegen-
agement (Pirooznia et al., 2020; Shin et al., 2011; Stevens eration, and ultimately behavioral impairments (Xilouri et al.,
et al., 2015). 2016). Selective blockage of CMA in excitatory neurons leads
Mice with neuronal loss of WIPI4, FIP200, and ATG9A, to a shift in the solubility of the metastable proteome (proteins
involved in early stages of autophagosome formation, or close to their solubility limit) (Bourdenx et al., 2021). Entrapment
WIPI3, involved in alternative macroautophagy, show accumula- of CMA substrate proteins within aggregates leads to loss of
tion of damaged mitochondria (Liang et al., 2010; Yamaguchi their function and defects in cellular metabolism, endocytosis,
et al., 2018, 2020; Zhao et al., 2015). Furthermore, neurons and cytoskeleton organization (Bourdenx et al., 2021).
may have upregulated other mitochondria quality control path- The tight communication between neurons and glia suggests
ways, such as mitochondrial-derived vesicles (MDVs) that carry that glial macroautophagy may have profound non-cell-autono-
oxidized proteins to lysosomes for degradation, thereby saving mous effects on neuronal function and health. Astrocytes
the entire organelle from clearance (Misgeld and Schwarz, promote neuronal health and survival by providing nutrients,
2017). Hence, bulk macroautophagy or MDVs may provide a controlling the uptake of neurotransmitters and ions and protect-
quality control mechanism that is constantly active in non-path- ing neurons upon injury. Astrocyte macroautophagy is emerging
ologic conditions, whereas mitophagy is trigged upon mild or se- as an important pathway to support neuronal health by regu-
vere mitochondrial stress (Misgeld and Schwarz, 2017; Yao lating the degradation of misfolded proteins (Ja €nen et al., 2010;
et al., 2020). Tang et al., 2008) and damaged mitochondria from degenerating
Synapses are dynamic structures highly dependent on neurons (Davis et al., 2014; Morales et al., 2020).
controlled turnover of their components. Autophagy is emerging Oligodendrocytes and Schwann cells are the myelin-produc-
as a crucial player in synapse formation, pruning, and plasticity ing cells of the central and peripheral nervous systems, respec-
(Birdsall and Waites, 2019; Stavoe and Holzbaur, 2019). Loss- tively. Studies using mice lacking ATG5 in oligodendrocyte
of-ATG7 studies revealed that autophagy is required in motor progenitor cells (OPC) demonstrated that macroautophagy is
neurons for presynaptic terminal formation, innervation of the essential for OPC survival, maturation, and proper myelination
neuromuscular junction (Rudnick et al., 2017), and in dopami- (Bankston et al., 2019). Similarly, Schwann-cell-specific removal
nergic neurons for synaptic vesicle degradation regulated by of ATG7 caused abaxonal accumulation of excess cytoplasm
active zone proteins, such as Bassoon and Piccolo (Hernandez and organelles, as well as abnormal myelination (Jang et al.,
et al., 2012; Okerlund et al., 2017). Subsequent studies in mice 2015), demonstrating that macroautophagy is essential for
lacking neuronal ATG5 revealed defective selective degradation proper myelination and insulation of axons.
of tubular ER in axons and increased excitatory neurotransmis- Microglia are the resident immune cells of the brain that
sion through excessive calcium release from ER stores (Kuijpers constantly sense the neural environment and clear debris to
et al., 2021). The relative contribution of the failure to degrade maintain homeostasis (Nimmerjahn et al., 2005). Amyloid-
synaptic vesicles versus calcium storage dysregulation to the b-induced neuroinflammation was aggravated upon microglial-
observed enhanced neurotransmission requires future investi- specific deletion of ATG7, resulting in excessive neuronal
gation. At the postsynaptic terminal, macroautophagy is damage (Cho et al., 2014), transition of microglia to a proinflam-
required for spine pruning, as cortical neurons lacking ATG7 matory status, defects in lipid homeostasis, and elevated tau
have an excessive number of dendritic spines (Tang et al., spreading (Xu et al., 2021). Similarly, loss of microglial ATG5 re-
2014). Macroautophagy also drives the degradation of the scaf- sulted in enhanced neuroinflammation and neurodegeneration in
fold proteins PSD95, PICK1, and SHANK3, and of AMPA recep- the striata of conditional knockout mice (Cheng et al., 2020), sug-
tors, leading to synapse destabilization (Compans et al., 2021; gesting that microglial macroautophagy plays a protective role
Nikoletopoulou et al., 2017; Shehata et al., 2012), and enables against aberrant microglial activation. Microglia have also been
retrograde transport of brain-derived neurotrophic factor shown to be involved in synaptic pruning (Paolicelli et al.,
(BDNF) (Kononenko et al., 2017), a key molecule involved in 2011). Neurons co-cultured with ATG7-deficient microglia
neuronal differentiation, survival, and synaptic plasticity. showed increased synaptic markers and dendritic spine density,
The role of macroautophagy in synaptic plasticity has not been as well as in immature dendritic filopodia (Kim et al., 2017). How-
fully elucidated. Acute Beclin 1 knockdown revealed the need for ever, ATG7 is also involved in LAP in peripheral macrophages
Neuron 110, March 16, 2022 941

ll
Review
(Heckmann et al., 2017); therefore, further studies are required to regulation of these processes. Macroautophagy both positively
determine whether deficiencies in macroautophagy or LAP are and negatively regulates apoptosis through degradation of
responsible for these changes. Interestingly, microglia from BCL-family proteins and their regulators (Fricker et al., 2018).
mice expressing human a-synuclein in neurons engulf and In neurons, BAX is the dominant executor of intrinsic
sequester a-synuclein by autophagosomes for degradation apoptosis. P53 upregulated modulator of apoptosis (PUMA,
(Choi et al., 2020). Together these studies show the importance also called BBC3) directly translocates BAX onto mitochondria
of functional macroautophagy in glia for neuronal function and in neuronal cells undergoing oxidative stress, thereby inducing
viability. apoptosis, a phenomenon that was rescued by PUMA knockout
Less is known about the function of CMA in glia. Neuronal CMA (Steckley et al., 2007). In HeLa cells, autophagy maintains low
blockage is associated with astrocyte enlargement and microglial PUMA mRNA levels through an unknown mechanism (Thorburn
activation, most probably because of neuronal dysfunction (Bour- et al., 2014). It is unclear whether similar regulation of PUMA ex-
denx et al., 2021; Xilouri et al., 2016). Mice with full-body CMA ists in neuronal cells.
blockage did not show overt astrogliosis or microglial activation The extrinsic apoptosis pathway contributes to pathogenesis
(Bourdenx et al., 2021), but a functional study is lacking. in neurological disorders. Neuronal specific deletion of cas-
pase-8 renders neurons resistant to TNF-a-ligation-induced
AUTOPHAGIC PROCESSES AND CELL DEATH apoptosis in vitro and increases neuron survival with reduced
PATHWAYS caspase-3 activation after acute brain injury (Krajewska et al.,
2011). The induction of apoptosis in primary cortical neurons
Although removal of excessive neurons is important for the by the neurotoxin 6-hydroxydopamine (6-OHDA) is rescued by
development of the nervous system, aberrant neuron death is knockdown of ATG5 or the macroautophagy inhibitor 3-methyl-
one of the principal causes of neurological disorders. The cell adenine (Chung et al., 2018).
death pathways that have been reported to interact with auto- The relation between CMA and apoptosis has been mostly stud-
phagy in the nervous system are discussed below. ied in cancer cells, where CMA prevents apoptosis through degra-
dation of cyclin D1, PUMA, or HMGB1 but facilitates immunogenic
Necrosis apoptosis by mediating surface exposure of calreticulin (reviewed
Necrosis, characterized by plasma membrane rupture can be in Arias and Cuervo, 2020). In untransformed cells, inhibition of
either regulated and genetically controlled, or unregulated (pas- CMA increases susceptibility to stressors and leads to apoptosis,
sive). Multiple types of regulated necrosis have been identified to but the molecular mechanisms remain poorly understood.
cause neuronal cell death, including necroptosis, ferroptosis, py-
roptosis, and parthanatos (Fricker et al., 2018). Necroptosis is Pyroptosis
mediated by activities of receptor interacting protein kinase 1 Pyroptosis is a form of cell death seen in many common neurolog-
(RIPK1), RIPK3, and mixed lineage kinase-domain-like pseudoki- ical diseases, such as AD and Parkinson disease (PD), that mani-
nase (MLKL) and has been reported to regulate axon degeneration fests with inflammasome-mediated release of caspase-1 from
induced by glutamate excitotoxicity and contribute to pathologies affected cells. Macroautophagy activation protects against this
in conditions like ALS and AD (Degterev et al., 2019). P62 interacts form of cell death in mouse models via diverse pathways, including
with RIPK1 on early autophagosome structures to form the ne- degradation of a key pyroptosis mediator NLRP3 (Wu et al., 2021).
crosome and induce necroptosis in response to TNF-related In this way, autophagy may also buffer neuroinflammation, a prev-
apoptosis-inducing ligand (TRAIL) in mouse prostate cells. Knock- alent process in different neurodegenerative conditions.
down of P62 switches the cell death to TRAIL-induced apoptosis
by blocking the formation of necrosome (Goodall et al., 2016). Autophagic cell death and autosis
Usually, macroautophagy promotes cell survival following
Ferroptosis stress/nutrient limitation by recycling cellular components and
Ferroptosis is an iron-dependent form of cell death which occurs providing energy. However, in ischemia/hypoxia and stroke,
when the phospholipid hydroperoxide (PLOOH) and lipid radi- macroautophagy has been reported to lead to cell death, termed
cals overwhelm their scavenging systems. Agents that inhibit fer- autophagic cell death (ACD). The main morphology of ACD is the
roptosis improve neuronal survival in multiple neurodegenera- accumulation of vacuoles with increased macroautophagy flux
tion models (Zheng and Conrad, 2020), and ferroptosis is and is rescued by knockdown or inhibition of autophagic pro-
involved in glial to neuron conversion after traumatic brain injury teins (Galluzzi and Green, 2019). However, much of the literature
(Gascón et al., 2016). Macroautophagy promotes ferroptosis in this domain has caveats, including the use of imprecise chem-
through ferritinophagy (Yang et al., 2019), since free iron is ical tools to manipulate autophagy and difficulties measuring au-
released from ferritin-bound iron via the lysosome. CMA also tophagic flux versus steady-state levels of autophagosomes
promotes ferroptosis by degrading glutathione peroxidase 4 in vivo. For example, autophagic flux can be impaired by defects
(GPX4), which catalyzes the reduction of lipid peroxides and pre- downstream of autophagosome formation, which lead autopha-
vents ferroptosis (Wu et al., 2019). gosome accumulation. Furthermore, a reduction in cell death in
such scenarios in macroautophagy knockout cells means that
Apoptosis autophagy is required for the death process but not that auto-
BCL-family proteins stimulate or inhibit macroautophagy and phagy is causing the cell death. To robustly support ACD, one
apoptosis, and these activities are at the center of the mutual needs to show a reduction of cell death when the flux is
942 Neuron 110, March 16, 2022

ll
Review
normalized, and not when it is ablated. Furthermore, some mac- and feeding-fasting cycles are coupled to the central circadian
roautophagy genes may have roles in cell death unconnected clock in the suprachiasmatic nucleus. Circadian oscillations
with their autophagic functions. involve transcriptional circuits and non-translational controls,
Interestingly, in all the ACD cases reported, inhibition of lyso- such as phosphorylation, which synchronize sleep/wake cycles,
some function fails to rescue cell death, suggesting that ACD food intake, and cellular bioenergetics (Reddy and Rey, 2014).
may be an autophagy-independent pathway under the control Food intake occurs during wake cycles and autophagy is
of autophagy machinery. Moreover, no common upstream initi- elevated during fasting (sleep). Recent work has shown that
ator-signaling pathway has been found (Galluzzi and TFEB and TFE3 control the rhythmic induction of their transcrip-
Green, 2019). tional target genes involved in macroautophagy and lysosomal
biogenesis during the light phase (sleep). Liver or muscle-spe-
ROLE OF DIFFERENT AUTOPHAGY PATHWAYS IN cific knockouts of both TFEB and TFE3 in mice results in loss
ENABLING NEURONAL FUNCTIONS of the diurnal macroautophagy cycle. TFEB and TFE3 were
shown to directly regulate the expression of Rev-erba (Nr1d1),
Autophagy plays a role in the structural reorganization of a transcriptional repressor component of the core clock machin-
neuronal circuits via axonal growth, dendritic spine formation ery also involved in the regulation of whole-body metabolism and
and pruning, synaptic assembly, and vesicle turnover (Fleming macroautophagy (Pastore et al., 2019).
and Rubinsztein, 2020; Kulkarni and Maday, 2018; Lieberman A dual interplay between circadian rhythms and CMA has also
and Sulzer, 2020). These autophagy-driven structural changes been recently reported whereby CMA displays central and pe-
have a major impact on neuronal functions. ripheral circadian activity and, at the same time, contributes to
the regulation of circadian cycling through degradation of com-
Learning and memory ponents of the clock machinery (Juste et al., 2021). Disruption
In hippocampal neurons, macroautophagy is upregulated during of CMA in vivo and the subsequent impaired degradation by
learning and memory consolidation. Macroautophagy inhibition CMA of the positive elements Bmal1 and Clock and the regula-
in the hippocampus of young mice affects their performance in tory element Rev-erba, leads to temporal shifts and amplitude
different behavioral tests, indicating a deficit in the formation of changes of the clock-dependent transcriptional program and
novel memories (Glatigny et al., 2019). The mTORC1 complex fragmented circadian patterns. In contrast to the modulatory ef-
is known to be overactivated in humans with fragile X syndrome fect of TFEB on circadian cycling, the CMA-dependent regula-
(Hoeffer et al., 2012). In mouse models, this hyperactivation de- tion of the clock is nutrient independent.
creases macroautophagy, increases dendritic spine density with
aberrant morphology, and leads to exaggerated LTD in hippo- Suggested links with psychiatric diseases
campal neurons associated with impaired novel object recogni- Recent studies have provided some support for the hypothesis
tion (Yan et al., 2018). that altered neuronal macroautophagy may contribute to
Since hippocampal macroautophagy declines with age, pro- depression, bipolar disorder, and schizophrenia. Autophagy-
moting macroautophagy has been investigated as a mechanism inducing drugs acting via independent pathways have antide-
to improve memory in aged animals. Injection of plasma from pressant-like properties in mice (Kara et al., 2013, 2018), and
young mice into older mice improves their memory in a macroau- numerous clinically prescribed anti-depressants with diverse
tophagy-dependent fashion (Glatigny et al., 2019), possibly via pharmacological activities enhance macroautophagy (reviewed
osteocalcin, a blood-brain barrier penetrant, bone-derived circu- in Gassen and Rein 2019). Although there has been little human
lating molecule previously demonstrated to act as a hormonal clinical research to support these findings, therapeutic concen-
regulator of hippocampal memory (Obri et al., 2018). However, trations of paroxetine and amitriptyline increase expression of
upregulation of macroautophagy may not be a panacea for all macroautophagy components (Beclin1, phosphor-AKT, and
memory deficits. For example, in primary neuron cultures, treat- LC3-II) in blood cells of patients and these changes predict clin-
ment with AICAR, a cell-permeable nucleoside used to induce ical improvement (Gassen et al., 2014). Similarly, in a small study
AMPK hyper-activation, led to macroautophagy-dependent in patients with major depressive disorder, serum levels of Beclin
loss of pre- and postsynaptic markers and a decline in neuronal 1 were higher in responders to selective serotonin reuptake in-
network function (Domise et al., 2019), suggesting that elevated hibitors than non-responders (He et al., 2019).
macroautophagy may be as damaging as reduced autophagy A smaller but growing body literature provides some support for
and that maintaining the balance of autophagic flux is crucial. a link between autophagy and schizophrenia. When mutated, dis-
Whole-body CMA-deficient mice have both memory and mo- rupted-in-schizophrenia 1 (DISC1) confers susceptibility to psy-
tor-coordination dysfunction, while blockage of CMA only in chiatric illness. DISC1 contains an LC3-interacting region (LIR)
excitatory neurons resulted mostly in impaired short-term mem- motif and, when overexpressed, enhances mitophagy (Wang
ory (Bourdenx et al., 2021). et al., 2019b). In post-mortem samples, transcriptomic analysis
revealed overrepresentation of genes that regulate altered
Sleep and circadian rhythm neuronal macroautophagy with downregulation of expression
Many neurodegenerative disorders are associated with altered observed in cortical and hippocampal areas in schizophrenic pa-
or poor sleep. Chronic sleep deprivation increases amyloid-b tients (Ryskalin et al., 2018). In addition, exome sequencing iden-
and tau in interstitial fluid and is associated with increased pa- tified four rare ULK1 variants significantly associated with schizo-
thology in mouse models (Holth et al., 2019). Daily sleep-wake phrenia in a case-control study (Al Eissa et al., 2018).
Neuron 110, March 16, 2022 943

ll
Review
Aging summarizes a more comprehensive, although not exhaustive,

Aging is a major risk factor for human neurodegenerative disease. list of autophagy-related genes associated with neurodegenera-
Autophagy appears to decline with age in many organisms (Han- tive disorders and the autophagic disruption caused by some
sen et al., 2008). Age-dependent decreases have been reported common neurodegenerative disease genes is summarized in
for macroautophagy gene transcripts in brains from Drosophila (Si- Figure 4. We have not reviewed all neurodegenerative disease
monsen et al., 2008) and humans (Lipinski et al., 2010), in mouse genes causing autophagy defects in the text, as extensive reviews
retinas (Rodrı́guez-Muela et al., 2013), and in autophagy proteins have been published previously (Menzies et al., 2017; Stamatakou
in mouse hypothalamus and hippocampus (Glatigny et al., 2019; et al., 2020).
Kaushik et al., 2012). Changes in lysosomal abundance with age
have been extensively documented in multiple peripheral tissues Mutations in core autophagy genes
in different experimental models (reviewed in Nixon, 2020), but Mutations in core macroautophagy genes have been identified
expansion of these compartments with age is not a universal in relatively few human neurodegenerative diseases. This may
feature, since recent studies in C. elegans have revealed age- be because core macroautophagy components are vital for
dependent decreases in lysosome and autophagosome abun- cellular homeostasis and may cause early lethality if mutated.
dance in tissues, such as intestines, muscles, and neurons (Chang A recent study identified recessive mutations in ATG7 in 12
et al., 2017). This decrease in abundance could explain the re- patients from 5 families with a range of neurodevelopmental
ported decreased macroautophagic activity in aged C. elegans disorders affecting the cerebellum and corpus callosum with
(Wilhelm et al., 2017), and it is consistent with the decline in auto- additional muscle, and endocrine involvement as well as facial
phagy flux and autophagosome biogenesis observed in mouse dysmorphism. While fibroblasts from one family had no obvi-
brains (Park et al, 2021). The progressive decline in macroautoph- ously detectable LC3-II, those from other families showed
agy with age can predispose to toxic protein and organelle accu- LC3-II conjugation, indicative of some functional autophagy.
mulation in neurons and compromise neuronal health. Indeed, im- Furthermore, in the family where no LC3-II was detected, au-
pairing autophagy reduces lifespan in C. elegans, Drosophila, and tophagosomes were evident in muscle biopsies (Collier et al.,
mice, while induction of macroautophagy extends longevity in 2021). Hence, further analysis is needed to determine whether
these organisms (Hansen et al., 2018). the mutations result in a complete loss of function and
CMA activity decreases with age in most organs and tissues, whether there is compensation from non-canonical auto-
predominantly due to reduced stability of LAMP2A at the lysophagy. Homozygotes with a mutation in ATG5 (E122D) mani-
somal membrane of old organisms (Kaushik et al., 2021). In pe- fest with childhood ataxia and cells derived from these pa-
ripheral tissues, reduced CMA with age contributes to loss of tients display decreased autophagic flux and reduced
proteostasis, metabolic derangements, immune senescence, conjugation of ATG12 to ATG5 (Kim et al., 2016). X-linked
and loss of stemness, all considered hallmarks of aging. dominant mutations in another core autophagy gene,
Conversely, genetic restoration of the LAMP2A defect in old or- WDR45 (encoding protein WIPI4) cause human b-propeller-
ganisms has proven sufficient to prevent proteotoxicity, improve protein-associated neurodegeneration (BPAN) mainly in fe-
the organismal response to stress, and restore organ function males (Saitsu et al., 2013) and decreased stability of WIPI4
(Kaushik et al., 2021). Although changes in CMA activity with and the accumulation of aberrant early autophagic structures
age in neurons are still poorly characterized, elevated levels of were observed in patient-derived lymphoblastoid cells. An
neuronal nitric oxide synthase, previously associated with autosomal recessive missense mutation in WIPI2 results in se-
neuronal aging, have demonstrated sufficient to reduce neuronal vere syndromic cognitive impairment and loss of brain volume
LAMP2A levels (Valek et al., 2019). (Jelani et al., 2019).
Most studies on autophagy in the aging brain have followed
changes on steady-state markers due to the difficulties of Mutations in genes involved in early stages of
measuring autophagy flux in live organisms. The development autophagosome formation
of mouse models constitutively expressing fluorescent probes Several neurodegenerative disease-causing mutations have
to follow bulk macroautophagy (Lopez et al., 2018), selective been identified in genes involved in membrane trafficking events
macroautophagy (mitophagy [Sun et al., 2015] or CMA [Dong required for autophagosome biogenesis. A mutation in VPS35
et al., 2020]) opens up the possibility of tracking changes in the dy- (D620N), a core retromer component, has been described in
namics of these processes with age. For example, studies in a mi- PD patients and in subsequent studies was shown to cause
tophagy reporter mouse have demonstrated reduced mitophagy ATG9 mislocalization (Zavodszky et al., 2014; Zimprich et al.,
flux in aged hippocampal pyramidal neurons (Sun et al., 2015). 2011). Similarly, an ATG9 trafficking defect was observed in cells
derived from patients with early-onset progressive spastic para-
AUTOPHAGY PATHWAYS AND NEURODEGENERATIVE plegia (SPG47 and SPG52), which are deficient for AP-4 pathway
DISEASES function (Davies et al., 2018).
Mutations in genes encoding proteins involved at all steps in Mutations in genes involved in substrate recognition
the macroautophagy pathway are implicated in different neurode- and selective autophagy
generative diseases. Often, one mutation can affect macroau- Mutations in the autophagy receptor P62 have been identified
tophagy at multiple stages. This section describes defects asso- in cases of familial and sporadic ALS and frontotemporal lobar
ciated with selected important examples, while Table 1 degeneration (FTLD) (reviewed in Deng et al., 2017),
944 Neuron 110, March 16, 2022

Review
Table 1. Mutations in neurodegeneration-related genes that affect macroautophagy
Stage of the autophagy pathway were a Cellular phenotype upon mutation or loss of
Gene/protein Neurodegenerative disease protein acts function of a protein
Core macroautophagy
ATG5/Autophagy-related 5 Hereditary childhood ataxia Early phagophore formation and elongation Decreased autophagosome formation
caused by weak binding of ATG5 to ATG12
(Kim et al., 2016)
WIPI2/WD repeat domain Severe cognitive impairment Early phagophore formation and elongation Decreased autophagosome formation
phosphoinositide-interacting protein 2 caused by reduced binding of WIPI2b to
ATG16L1, as well as ATG5-12 (Jelani
et al., 2019)
WDR45/WD repeat domain Beta-propeller-protein-associated Early phagophore formation and Impairment in autophagy flux and an
phosphoinositide-interacting protein neurodegeneration (BPAN, NBIA, SENDA) elongation/autophagosome-lysosome accumulation of LC3-positive
4 (WIPI4) fusion autophagosome membranes (Saitsu et al.,
2013), and ubiquitin-positive aggregates
(Zhao et al., 2015); impaired formation of
fusion machinery (Ji et al., 2021)
Other genes that impact autophagy
ATXN3/Ataxin-3 Spinocerebellar ataxia type 3 (SCA3) Early phagophore formation Impaired initiation in starvation-induced
autophagy (Ashkenazi et al., 2017)
GJB1/gap junction protein connexin 32 Charcot-Marie-Tooth type 1 (CMT1) Autophagosome formation Reduced autophagosome formation
(Bejarano et al., 2014)
VPS35/Vacuolar protein sorting-associated Parkinson disease (PD) Autophagosome formation and elongation Abnormal trafficking of mATG9 and
protein 35 autophagy impairment (Zavodszky
et al., 2014)
EPM2A, EPM2B/Laforin, Malin Lafora disease Autophagosome formation and elongation Decreased LC3 lipidation and increase in
p62 (Aguado et al., 2010); defective
regulation of PI3KC3 complex; decreased
PI(3)P levels (Sanchez-Martin et al., 2020)
TECPR2/Tectonin beta-propeller repeat- Spastic paraplegia type 49 (SPG49) Phagophore membrane elongation Decrease in LC3 lipidation and levels of LC3
containing 2 TECPR2 and WIPI2 (Oz-Levi et al., 2012; Stadel
et al., 2015)
AP4S1/AP-4 complex subunit sigma-1 Hereditary spastic paraplegia Phagophore membrane elongation Deficiency causes mis-sorting of mATG9
(SPG47, SPG52) (Davies et al., 2018)
Neuron 110, March 16, 2022 945
PICALM/phosphatidylinositol-binding Alzheimer disease (AD) Autophagosome formation/maturation Autophagosome formation and maturation
clathrin assembly protein dysfunction; impaired APP cargo
recognition (Moreau et al., 2014; Tian
et al., 2013)
C9ORF72/Hexanucleotide repeat Amyotrophic lateral sclerosis (ALS); Autophagosome formation/maturation Impaired autophagy flux (Farg et al., 2014);
expansions in a non-coding region of frontotemporal dementia (FTD) impaired trafficking of the ULK1 initiation
chromosome 9 open reading frame 72 complex to the phagophore (Webster
ll
et al., 2016)
(Continued on next page)
946 Neuron 110, March 16, 2022
Table 1. Continued
ll
SNCA/a-synuclein Parkinson disease (PD) Autophagosome formation/maturation Impaired autophagosome transport (Tanik
et al., 2013; Volpicelli-Daley et al., 2014);
abnormal mATG9 trafficking (Winslow et al.,
2010); disturbed TFEB-mediated lysosomal
biogenesis (Decressac et al., 2013)
VCP/Valosin-containing protein VCP Inclusion body myopathy with early-onset Autophagosome formation/maturation Loss of ATPase activity causes impaired
Paget disease and frontotemporal autophagosome formation (Hill et al., 2021);
dementia (IBMPFD), amyotrophic lateral impaired autophagosome maturation (Ju
sclerosis (ALS), Charcot-Marie-Tooth type et al., 2009; Tresse et al., 2010); recruited to
2 (CMT2), tauopathies damaged lysosomes to facilitate lysophagy
(Papadopoulos et al., 2020)
SPG11/spatacsin Hereditary spastic paraplegia (SPG11) Autophagosome maturation Impaired autophagic lysosome reformation
(Chang et al., 2014; Vantaggiato et al., 2019)
ZFYVE26/spastizin (SPG15) Hereditary spastic paraplegia (SPG15) Autophagosome maturation Disrupts interaction with Beclin 1 which
impairs autophagosome maturation
(Vantaggiato et al., 2013) and lysosomal
biogenesis (Chang et al., 2014; Vantaggiato
et al., 2019)
RAB7A/Ras-associated protein Rab-7a Charcot-Marie-Tooth type 2 (CMT2) Autophagosome maturation Impaired autophagosome-lysosome fusion
(Ganley et al., 2011)
ALS2/ALSIN Amyotrophic lateral sclerosis (ALS) Autophagosome maturation Impaired autophagosome fusion with
endosomes through its regulation of RAB5
(Ravikumar et al., 2008)
UBQLN2/Ubiquilin 2 Amyotrophic lateral sclerosis (ALS) Autophagosome formation/maturation/ Impaired autophagosome maturation
lysosomal function (N’Diaye et al., 2009); impaired LC3
lipidation (Rothenberg et al., 2010);
impaired autophagic flux caused by
lysosomal defect (Sxentu €rk et al., 2019; Wu
et al., 2020); decrease in the levels of
autophagic proteins (Chen et al., 2018)
HTT/Huntingtin Huntington’s disease Autophagosome formation/ Impaired cargo recognition (Martinez-
autophagosome-lysosome fusion/cargo Vicente et al., 2010; Ochaba et al., 2014; Rui
recognition et al., 2015); decreased autophagosome
transport (Wong and Holzbaur, 2014b);
impaired starvation-induced autophagy
initiation (Ashkenazi et al., 2017)
CHMP2B/Charged multivesicular body Amyotrophic lateral sclerosis (ALS), Autophagosome-lysosome fusion required Impaired autolysosome formation
protein 2b frontotemporal dementia (FTD) for eMI (Filimonenko et al., 2007; Lee et al., 2007)
MAPT/microtubule-associated protein tau Alzheimer disease (AD), tauopathies Autophagosome-lysosome fusion Dysfunction of the retrograde axonal
Review
transport of autophagosomes (Butzlaff
et al., 2015; Majid et al., 2014)
Review
Table 1. Continued
SNX14/Sorting nexin-14 Spinocerebellar Ataxia Type 20 (SCAR20) Autophagosome-lysosome fusion Impaired autophagosome clearance (Akizu
et al., 2015); impaired lysosomes (Bryant
et al., 2018)
DCTN1/Dynactin Amyotrophic lateral sclerosis (ALS) Autophagosome-lysosome fusion Impaired autophagosome-lysosome fusion
(Ravikumar et al., 2005)
PSEN1/Presenilin 1 Alzheimer’s disease (AD) Lysosomal function Impaired autophagosome-lysosome fusion
and defective lysosomal acidification
(Chong et al., 2018; Lee et al., 2010; Zhang
et al., 2012)
GBA/Lysosomal acid glucosylceramidase Parkinson disease (PD) Lysosomal function Impaired autophagy caused by lysosomal
dysfunction (Murphy et al., 2014); impaired
removal of dysfunctional mitochondria by
mitophagy (Li et al., 2019b)
ATP13A2/Polyamine-transporting Parkinson disease (PD) Lysosomal function Impaired lysosome acidification (Bento
ATPase 13A2 et al., 2016; Dehay et al., 2012)
SYT11/synaptotagmin 11 Parkinson disease (PD) Lysosomal function Lysosomal dysfunction ((Bento et al., 2016)
GRN/Progranulin Frontotemporal lobar degeneration (FTLD) Lysosomal function Impaired lysosomal function (Logan et al.,
2021); deficiency in neurons increases
autophagy flux and causes abnormally
enlarged lysosomes (Elia et al., 2019)
FIG4/Polyphosphoinositide Charcot-Marie-Tooth disease 4J (CMT4J), Lysosomal function Impaired production of PI(3,5)P(2), impaired
phosphatase FIG4 Amyotrophic lateral sclerosis 11 (ALS11), endo-lysosomes, accumulation of p62
Yunis-Varon syndrome (YVS) (Ferguson et al., 2009)
VPS13D/Vacuolar protein sorting 13D ataxia and/or spastic paraplegia ? Accumulation of damaged mitochondria
(Anding et al., 2018)
PEX13/Peroxisomal membrane Human peroxisome biogenesis ? Impaired mitophagy without disruption of
protein PEX13 disorders (PBDs) general autophagy (Lee et al., 2017)
Macroautophagy adapters
SQSTM1/Sequestosome-1 (p62) Amyotrophic lateral sclerosis (ALS), Cargo recognition Impaired recruitment into autophagosomes
Frontotemporal lobar degeneration (FTLD) (Goode et al., 2016); impaired cargo
recognition and protein clearance (Gal
Neuron 110, March 16, 2022 947
et al., 2009)
OPTN/Optineurin Amyotrophic lateral sclerosis (ALS) Cargo recognition/autophagosome Impaired cargo recognition and protein
formation and maturation clearance (Shen et al., 2015); impaired
ATG5-ATG12-ATG16L recruitment to
phagophore and decreased formation
(Bansal et al., 2018; Song et al., 2018);
impaired autophagosome trafficking to
ll
lysosomes (Sundaramoorthy et al., 2015;
Tumbarello et al., 2012)
ll
Review
leading to disrupted degradation of SOD1 and TDP-43 (Gal

et al., 2009).
Cellular phenotype upon mutation or loss of
downstream of FAM134B during ER-phagy
autophagosome formation (Liu et al., 2021)

(Chen et al., 2019); impaired recruitment of
Impaired mitophagy (Moore and Holzbaur,
2016; Pilli et al., 2012; Richter et al., 2016)
(Liang et al., 2018); impaired association

binding to autophagy modifiers LC3 and
Mutations in FAM134B (also called RETREG1), an ER-phagy
with GABARAP and impaired ER-phagy

Impaired ER-phagy though decrease
receptor, cause hereditary sensory and autonomic neuropathy
ULK1 complex to ER-specific site of
Impaired mitophagy (reviewed in Ge
Impaired mitophagy (reviewed in Ge

GABARAP (Bhaskara et al., 2019;
type II (HSAN II) and compromise ER-phagy, leading to ER
Depletion inhibits ER-phagy, acts

expansion (Bhaskara et al., 2019; Khaminets et al., 2015). Muta-
tions in ATL3 that cause hereditary sensory and autonomic neu-
ropathy type I (HSAN I) impair starvation-induced ER-phagy
Khaminets et al., 2015)
through direct disruption of the association of ATL3 with

function of a protein
GABARAP (Chen et al., 2019).

OPTN mutations inhibit its ability to recruit LC3 to damaged
et al., 2020)
et al., 2020)
mitochondria and to induce mitophagy (Shen et al., 2015;
Wong and Holzbaur, 2014a), and ALS-associated mutations
in this kinase reduce binding of TBK1 to OPTN therefore
decreasing mitophagy (Richter et al., 2016).
Amplifies damage mitochondria detection
Sensor of mitochondrial stress/promotes
Stage of the autophagy pathway were a
Mutations in genes involved in autophagosome

Promotes efficient cargo recognition by
ER-phagy receptor/autophagy initiation

OPTN and regulates other autophagic
trafficking, maturation, and fusion with lysosomes

signal/promotes efficient mitophagy
Autophagosomes generated in axons rely on retrograde trans-

port to fuse with perinuclear lysosomes. Therefore, neurons
are particularly vulnerable to disruption in trafficking. Dynein-dy-
nactin is a molecular motor required for fast retrograde transport
of autophagosomes, organelles, RNAs, and proteins along mi-
efficient mitophagy
ER-phagy receptor
crotubules and is the target of mutations causing axonal Char-

cot-Marie-Tooth hereditary neuropathy type 2 (CMT2) and ALS
protein acts
(Puls et al., 2003). Defects in trafficking have also been associ-

proteins
ated with disease-causing mutations in a-synuclein (PD),

at ER
C9ORF72 (ALS), and with hyperphosphorylated tau (seen in

tauopathies, see Polygenic diseases).
Fusion events required for autophagosome maturation
involve many components of the endocytic pathway, such as
the small GTPase RAB protein family. Mutations in RAB7, en-
hereditary spastic paraplegia (HSP),
Amyotrophic lateral sclerosis (ALS)
coding the late endosomal RAB7A protein, cause Charcot-

Hereditary sensory and autonomic
hereditary sensory and autonomic
Marie-Tooth type 2B disease (Verhoeven et al., 2003). Similarly,

mutations in a RAB5 regulatory protein Alsin can result in
neuropathy type II (HSAN II)
Neurodegenerative disease
recessive ALS (Yang et al., 2001). ALS can be also caused by

Parkinson disease (PD)
Parkinson disease (PD)
mutations in CHMP2B, one of the subunits of the ESCRT-III

neuropathies (HSAN)
complex, which impair autophagosome maturation (Filimo-

nenko et al., 2007; Lee et al., 2007). Disruption to the ESCRT
machinery may also interfere with eMI by disrupting proper
LE/MVB biogenesis.
Mutations in genes involved in lysosomal function

Macroautophagy completion requires lysosomal digestion of au-
PRKN/E3 ubiquitin-protein ligase PARKIN
tophagic cargo and subsequent release of recycled metabolites.

The degradative capacity of lysosomes depends on low pH,
RETREG1/Reticulophagy regulator 1
which is mediated by vacuolar ATPase (vATPase). Mutations in

ATL1 and ATL3/Atlastin 1 and 3
genes associated with familial forms of neurodegeneration,

PINK1/serine/threonine-protein
TBK1/TANK-binding kinase 1
such as PSEN1 (AD) (Lee et al., 2010), a-synuclein (Decressac

et al., 2013), and ATP13A2 (PD) (Bento et al., 2016; Dehay
Continued
et al., 2012) affect lysosomal pH. Following autolysosome fusion

and cargo degradation, lysosomes undergo a process called
reformation. SPG11 and SPG15, encoded by genes mutated in
kinase PINK1
Gene/protein
hereditary spastic paraplegia, have been implicated in this pro-

(FAM134B)
Table 1.
cess and loss of SPG11 or SPG15 result in the depletion of lyso-

somes capable of fusing with maturing autophagosomes (Van-
taggiato et al., 2019).
948 Neuron 110, March 16, 2022

ll
Review
Figure 4. Overview of the role of macroautophagy in the nervous system in health and neurodegeneration
Autophagy is fundamental to sustain the homeostasis and function of the CNS. Perturbations in the macroautophagy pathway at different stages have been
observed during neurodegeneration and distinct disease-associated genes are also key contributors to macroautophagy dysfunction. Defective autophagy
compromises protein clearance and organelle turnover, leading to the accumulation of toxic proteins and damaged cellular components that finally alter neuronal
function and induce neuronal loss.
Mutations in genes involved in CMA that regulate splicing of this gene are needed to determine
Loss-of-function mutations in LAMP2 cause Danon disease that whether these differences are linked to specific gene mutations.
manifests with cardiomyopathy, myopathy, variable cognitive Further studies are also needed for the heterozygous variant in
impairment, and with progressive retinal degeneration (Cenacchi the LAMP2 gene promoter that significantly reduces LAMP2 tran-
et al., 2020). Most mutations in this disease occur in the part of the scription in a PD patient (Sala et al., 2016). Mutations in different
gene common to all spliced LAMP2 protein variants. Since only proteins related to PD and frontotemporal dementia associated
the LAMP2A splice variant of this gene is required for CMA, with reduced CMA activity are summarized in Table 2.
whereas the other variants LAMP2B and LAMP2C contribute to
macroautophagy and lysosomal degradation of DNA and RNA, POLYGENIC DISEASES
respectively, the mutations will cause defects in multiple types
of autophagy. Interestingly, expression of each of the LAMP2 Tauopathies and AD
proteins has been shown to be differentially affected in PD pa- Tauopathies are characterized by the intracellular accumulation
tients brains, with the earlier changes occurring in LAMP2A and aggregation of tau into paired helical filaments and neurofi-
(Sala et al., 2016). However, further studies on the mechanism brillary tangles and include frontotemporal dementias (FTDs),
Neuron 110, March 16, 2022 949

ll
Review
Table 2. Mutations in neurodegeneration-related genes with impact on CMA

Gene Mutation/s Associated disease Effect on CMA References
SNCA A53T PD Blocks CMA uptake Cuervo et al. (2004)
A30P
LRRK2 G2019S PD Reduces LAMP2A stability and blocks CMA Orenstein et al. (2013)
R1441C uptake
D1994A
VPS35 D620N PD Reduces LAMP2A stability Tang et al. (2015)
UCH-L1 I93M PD Blocks CMA substrates degradation Kabuta et al. (2008)
LAMP2 LAMP24127A>C PD Reduces LAMP2A transcription Pang et al. (2012)
MAPT P301L FTD Blocks CMA degradation Caballero et al. (2018)
AD, progressive supranuclear palsy (PSP), and corticobasal this dependence on lysosomal pH for uptake through CMA, so
degeneration (CBD). far only described for tau, explains tau’s highly efficient degra-
Multiple studies demonstrate the roles of different types of dation by this pathway (Caballero et al., 2021) and highlights
autophagy in the degradation of tau. Tau colocalizes with LC3 that the reported impaired lysosomal acidification in some
and P62 in post-mortem brains of familial AD, CBD, and PSP pa- forms of familial AD could also lead to reduced tau degradation
tients and the expression of P62 is reduced in AD patients (Liu by CMA (Wolfe et al., 2013).
et al., 2017). Tau associates with the autophagy cargo receptors Tau can also be a substrate of KFERQ-selective eMI, although,
NDP52 and OPTN, which also colocalize with neurofibrillary tan- as is the case for CMA, pathogenic tau mutations and PTMs
gles and dystrophic neurites in AD patients (Osawa et al., 2011; inhibit eMI activity at different stages (i.e., substrate binding to
Xu et al., 2019). Clearance of tau variants associated with LE/MVB, internalization or degradation in the lumen) (Caballero
different tauopathies occurs via different autophagic routes (Ca- et al., 2018). As different types of autophagy can clear tau, this en-
ballero et al., 2018). For example, phosphorylation of tau inhibits ables re-routing of this aggregate-prone protein from one auto-
its degradation by macroautophagy and results in tau clearance phagy type to another when one of these routes is compromised.
via an endolysosomal pathway dependent on ESCRT complex For example, acetylated tau can be re-routed to eMI for degrada-
and the small GTPase RAB35 (Vaz-Silva et al., 2018). About tion when CMA is inhibited (Caballero et al., 2021). This re-routing
50% of tau is degraded by macroautophagy and the other of acetylated tau to eMI can lead to its extracellular release in exo-
50% is degraded by non-macroautophagy pathways (CMA somes through fusion of LE/MVBs with the plasma membrane
and eMI) (Caballero et al., 2021). Interestingly, tau acetylation, (Caballero et al., 2021). This may provide a mechanism to remove
a pathological post-translational modification, and pathogenic toxic products, such as acetylated tau, from neurons when they
mutations, such as the FTD-related mutation A152T, favor tau are unable to be degraded (Pérez et al., 2019) but may also
degradation by macroautophagy, whereas the P301L mutation contribute to disease progression through extracellular release
reduces overall tau degradation (Caballero et al., 2018). of pathogenic tau (Caballero et al., 2021). The factors that deter-
Compromised removal by CMA of pathogenic forms of tau, mine whether the eMI re-routed protein is degraded in LE/MVB or
including both mutant and post-translationally modified, is released extracellularly remain unknown.
further aggravated by the toxic effect that these proteins exert AD, the most common tauopathy and neurodegenerative dis-
on this process. In vivo, expression of pathogenic tau protein is order, is characterized by the accumulation of intracellular tau
sufficient to induce neuronal (but not astrocytic) specific inhibi- tangles, and extracellular amyloid-b deposits (Ab plaques). Mac-
tion of CMA (Bourdenx et al., 2021). Although direct evaluation roautophagy has been implicated in the production of amyloid-b
of CMA activity in human brain in a cell-type-specific manner is within the autophagic vesicles and its secretion to the extracel-
not currently possible, analysis of the transcriptional expression lular matrix, contributing to plaque formation in vivo in mice
of the components of the CMA network in the brain of AD pa- and Drosophila models of amyloid toxicity (Yu et al., 2004).
tients using single-nuclei RNA-seq demonstrated a neuronal Levels of Beclin 1 are decreased in patients with AD at early
specific transcriptional inhibition of CMA (Bourdenx et al., stages (Lachance et al., 2019), whereas Beclin 1 overexpression
2021) that correlated with the Braak stages of tau pathology. reduced amyloid aggregation in a mouse model of AD (Pickford
The reduction of CMA score was higher in excitatory than in et al., 2008). Microglial Beclin 1 modulates the inflammatory
inhibitory neurons, thus corresponding well with the higher response in Becn1+//APPPS1 mice (Houtman et al., 2019),
vulnerability to tau pathology of excitatory neurons. and microglial amyloid-b removal and phagocytosis is signifi-
The mechanisms behind tau’s toxicity on CMA are under cantly impaired in Beclin 1+/ mice (Lucin et al., 2013). Amy-
investigation, but at least for acetylated and P301L tau, translo- loid-b proteins also induce the accumulation of deficient mito-
cation of these proteins through the LAMP2A multimeric com- chondria, driven by the depletion of cytosolic Parkin and
plex is compromised due to loss of their pH-dependent interac- PINK1 accumulation, resulting in defective mitophagy (Cummins
tion with luminal HSC70 (Caballero et al., 2021). Persistent et al., 2019; Fang et al., 2019). TREM2, an inflammation-linked
occupancy of the CMA translocation complex by pathogenic risk factor for late-onset AD (Jonsson et al., 2013), is also asso-
tau blocks degradation of other CMA substrates. Interestingly, ciated with mTOR pathway dysregulation in AD, where there is
950 Neuron 110, March 16, 2022

ll
Review
also downregulation of the Beclin 1-PI3K and ULK1/2 complexes (CTF) of APP (C99—originating from b-secretase cleavage) in-
(Lachance et al., 2019). duces autophagy-lysosome impairments independently of amy-
Brains from AD patients show a selective loss of nuclear TFEB loid-b accumulation (Lauritzen et al., 2016). Interestingly, APP
in the hippocampus, negatively correlating with the severity of the CTFs contain a KFERQ motif (763KFFEQ768) that could be utilized
neuropathology, and reduced expression of TFEB target genes is for its degradation through CMA or eMI (Park et al., 2016a).
also observed in AD patient fibroblasts and iPSC-derived human Consistent with that notion, CMA blockage in a genetic AD
AD neurons (reviewed in Cortes and La Spada, 2019). mouse model caused CTF accumulation (Bourdenx et al., 2021).
Familial AD and genetic risk factors Parkinson disease

Mutations in the genes encoding amyloid precursor protein (APP) PD is characterized by the loss of dopaminergic neurons in the
and presenilin (PSEN) cause autosomal dominant early-onset substantia nigra, the presence of intraneuronal inclusions
forms of AD (reviewed in (Raybould and Sims, 2021). PSEN1 mu- (Lewy bodies, LBs) in neuronal soma and neurites enriched
tations increase lysosomal pH by deregulating the maturation of with filamentous forms of a-synuclein (Spillantini et al., 1997).
lysosomal v-ATPase and consequently reduce autophagic cargo a-Synuclein has been proposed to play roles in synaptic func-
degradation (Nixon, 2013). The APOE4 allele, involved lipid traf- tion, its levels are a major determinant of PD severity, and multi-
ficking and metabolism, is the most common AD genetic risk fac- plications of the SNCA (a-synuclein-encoding) locus cause auto-
tor (Bu, 2009). APOE4 carriers have more pronounced reductions somal dominant forms of PD. a-synuclein can be cleared by the
in LC3, P62, and LAMP1 compared with APOE3 carriers (Parcon proteasome, macroautophagy, and CMA (Cuervo et al., 2004;
et al., 2018). In astrocytes from mice expressing human APOE4 Webb et al., 2003). a-synuclein accumulation compromises au-
variant, autophagosome formation and cargo degradation were tophagic flux, as the presence of inclusion bodies containing
defective (Simonovitch et al., 2016). Levels of phosphatidylinosi- a-synuclein impairs autophagosome maturation and fusion
tol biphosphates, essential for autophagic function, are reduced with lysosomes (Tanik et al., 2013). Indeed, disruptions in the
in post-mortem human brain tissues of APOE4 carriers (Dall’Armi macroautophagy machinery appear to be central to PD patho-
et al., 2013) and in primary neurons and astrocytes derived from genesis, with different PD-causing mutations affecting various
knockin mice expressing human APOE4 (Zhu et al., 2015). stages of the autophagy itinerary (Karabiyik et al., 2017).
APOE4 may also affect the expression of P62, LAMP2, and a-synuclein overexpression in mammalian cells and trans-
MAP1LC3B by competing with TFEB for the binding to the genic mice compromises autophagosome biogenesis by inhibit-
CLEAR domains in their promoters (Parcon et al., 2018). ing the GTPase RAB1 leading to mislocalization of ATG9 (Win-
The impairment of macroautophagy in AD may also be a slow et al., 2010). The expression of mutant a-synuclein (A53T)
consequence of variants in genes with a functional role in macro- leads to an accumulation of mitochondria-containing autopha-
autophagy, such as SORL1, PICALM, and PLD3 (see Table 1 for gosomes in PC12 cells (Stefanis et al., 2001) and to increased
wild-type function). Reduced levels of SORL1, which regulates autophagosomal engulfment of healthy, polarized mitochondria
protein trafficking between the trans-Golgi network, are in primary neurons, causing an abnormal clearance of functional
observed in iPSC-derived neurons from AD patients (Hung et mitochondria and therefore, a bioenergetic deficit (Choubey
al., 2021). Phosphatidylinositol-binding clathrin assembly pro- et al., 2011). In addition, results from Drosophila suggest that
tein (PICALM) identified in a GWAS study in a locus associated a-synuclein expression impairs autophagic flux in aging adult
with AD risk, is abnormally cleaved in AD brains, and its levels neurons by disrupting the F-actin cytoskeleton (Sarkar
inversely correlate with LC3-II and Beclin 1 levels. In addition, et al., 2021).
alternative splicing of the protein correlates with tau aggregation Although CMA contributes to the clearance of a-synuclein in
and Braak stages (Raj et al., 2018). PICALM regulates endocy- primary cultured cells and in vivo (Cuervo et al., 2004), patho-
tosis of critical SNAREs involved in both autophagosome genic A53T and A30P mutant a-synuclein proteins are still tar-
biogenesis and degradation (Moreau et al., 2014). geted by HSC70 to lysosomes, but their abnormally enhanced
The link between macroautophagy and AD is further sup- interaction with LAMP2A and their oligomerization at the lyso-
ported by several genetic studies that associate autophagy- somal membrane disrupt the CMA translocation complex and
related genes with AD. Pathway enrichment algorithms block CMA of other substrate proteins (Cuervo et al., 2004).
analyzing the data from three GWAS studies found an enrich- CMA malfunction is not restricted to familial PD, as PTMs on
ment in autophagic and endolysosomal genes associated with a-synuclein can also compromise its CMA degradation (Marti-
genetic variants that increase risk of AD (Gao et al., 2018). nez-Vicente et al., 2008). While phosphorylation and covalent
Gradual loss of CMA with age may also become a risk factor oligomerization mask the KFERQ-like motif in a-synuclein (Kirch-
for AD. Thus, CMA blockage in a mouse model of AD accelerated ner et al., 2019) and disrupt its targeting to lysosomes, dopamine
tau phosphorylation and aggregation, tau propagation, and am- oxidation leads to formation of a-synuclein-dopamine adducts
yloid-b extracellular deposition (Bourdenx et al., 2021; Caballero that are still targeted to lysosomes where they disrupt CMA
et al., 2021). CMA deficiency increases similarity between the through similar mechanisms as the a-synuclein mutants (Marti-
proteomes of brains from mouse model of disease and AD pa- nez-Vicente et al., 2008).
tients, thus mimicking part of the disease usually missing in con- Alterations in CMA-related proteins have been reported in the
ventional models (Bourdenx et al., 2021). brains of familial and idiopathic PD patients. Reduced levels of
Although much interest has been focused on extracellular LAMP2A and HSC70 in the substantia nigra and amygdala of
fragments (amyloid-b 40 and 42), the C-terminal fragment PD brains occur early in the disease and correlate with
Neuron 110, March 16, 2022 951

ll
Review
a-synuclein accumulation (Scrivo et al., 2018). Reduced mRNA tin, resulting in increased fusion and autophagy flux (Borsche
levels for both proteins suggest that downregulated transcrip- et al., 2020).
tion, in addition to the physical blockage of CMA, may both Autosomal recessive mutations in PTEN-induced kinase 1
contribute to compromised CMA in PD. This reduced CMA in (PINK1 or PARK6) and Parkin (PARK2), key regulators of a
the PD brain has a negative impact in neuronal survival, in part, form of mitophagy, have been discussed above. Low CMA activ-
by reducing degradation of the transcription factor MEF2D, nor- ity in PD has also been linked to alteration of mitochondria dy-
mally degraded by CMA. Accumulation of the inactive form of namics. Failure to degrade PARK7/DJ1 through CMA leads to
MEF2D prevents its protective function in these cells (Yang its accumulation, disruption of mitochondrial homeostasis and
et al., 2009). The relation between PD and eMI has not been cell death (Wang et al., 2016). Similarly, MARCHF5, an E3 ubiq-
directly analyzed, but a recent study showing that a mutated uitin ligase required for mitochondrial fission, is a CMA substrate
form of a-synuclein accumulates in the LE/MVB and is secreted that upon CMA blockage gets stabilized, increasing mitochon-
in exosomes (Stykel et al., 2021) opens the possibility of a re- drial fission and altering mitochondrial homeostasis. Overex-
routing of a-synuclein from CMA to eMI, similar to the situation pression of LAMP2A in a 6-OHDA PD mouse model was suffi-
with tau upon CMA blockage (Caballero et al., 2021). cient to rescue its phenotype (Nie et al., 2020).
Increasing evidence suggests that other mutations causing fa- The reported interaction between UCH-L1 with LAMP2A,
milial PD also affect autophagic function. In an autosomal domi- HSC70, and HSP90 is abnormally enhanced in the case of the
nant form of PD, a mutation (D620N) in the vacuolar protein sort- PD-related UCH-L1 I93M mutant and results in reduced degrada-
ing 35 (VPS35), a component of the retromer complex, impairs tion of proteins, including a-synuclein via CMA (Scrivo et al., 2018).
macroautophagy (see Table 1). Mutations in the leucine-rich Similarly, although a fraction of cellular LRRK2 undergoes degra-
repeat kinase 2 (LRRK2) gene are responsible for most autosomal dation via CMA, mutant forms of LRRK2 block the formation of
dominant PD cases, increase phosphorylation of different RAB the LAMP2A translocation complex and degradation of other pro-
GTPases (Alessi and Sammler, 2018) and disrupt endosome- teins through CMA (Orenstein et al., 2013). In other instances,
to-lysosome trafficking. While the most common mutation reduced CMA by PD-related pathogenic proteins is a conse-
(G2019S) has been associated with a reduction of macroautoph- quence of a more general effect in the lysosomal compartment.
agy flux (Henry et al., 2015; Wallings et al., 2019), LRRK2 deletion This occurs with VPS35, whose deficiency or mutant form
in neurons increases both macroautophagy (through the regula- D620N reduces lysosomal levels of LAMP2A through its inefficient
tion of p62 phosphorylation) and lysosomal degradation (Park retrieval from the Golgi (Scrivo et al., 2018). Reduced enzymatic
et al., 2016b; Wallings et al., 2019). Contrary to this proposed activity of GBA1 reduces lysosomal levels of LAMP2A (Murphy
inhibitory role of LRRK2 in neurons, overexpression of LRRK2 et al., 2014), likely by inducing changes in the lipid composition
in microglial cells increased macroautophagy flux, while LRRK2 of the lysosomal membrane associated with increased levels of
silencing reduced degradation (Wallings et al., 2019). Further- cathepsin A, the enzyme that triggers LAMP2A degradation in ly-
more, the effect of LRRK2 may also differ depending on the sosomes (Kaushik and Cuervo, 2018). A similar destabilizing effect
type of autophagy. Thus, the LRRK2 G2019S mutant was also on lysosomal LAMP2A has been described for the loss-of-function
suggested to induce mitophagy in multiple studies by causing mutants of PARKK7/DJ1, although the mechanism behind this ef-
calcium imbalance, resulting in mitochondrial depolarization fect remains unknown (Xu et al., 2017).
(Cherra et al., 2013).
Heterozygous mutations in the gene encoding the lysosomal Amyotrophic lateral sclerosis
enzyme glucocerebrosidase 1 (GBA1) are among the most com- ALS is the most common adult-onset motor neuron disease
mon genetic risk factors for PD. iPSC-derived neurons from PD characterized by upper and lower motor neurons (MNs) degen-
patients with GBA1 mutations showed increased a-synuclein eration. While 90% of all ALS cases are sporadic (sALS), around
levels and macroautophagy and lysosomal defects, including 10% are due to a genetic mutation. To date, more than 20 genes
impaired fusion between autophagosomes and lysosomes have been associated with ALS (Mathis et al., 2019), including
(Schöndorf et al., 2014), further corroborated in neuroblastoma C9ORF72, TAR DNA-binding protein (TARDBP/TDP-43), P62
cells with nonsense mutations in GBA1 (Bae et al., 2015) and (SQSTM1), TANK-binding kinase 1 (TBK1), and optineurin
in GBA1-deficient cells (Magalhaes et al., 2016). (OPTN), whose mutations can result in autophagy and mitoph-
Mutations in ATP13A2/PARK9, which encodes a transmem- agy defects, and the accumulation of protein inclusions in familial
brane lysosomal P-type ATPase polyamine transporter, cause fa- ALS (fALS) patients.
milial Kufor-Rakeb syndrome with early-onset Parkinsonism and Hexanucleotide repeat expansions (HREs) in the 50 non-cod-
impair lysosomal function (Dehay et al., 2012). Loss of ATP13A2 ing sequence of the C9ORF72 gene have been identified as
causes a-synuclein accumulation in mammalian cells and in the most common cause of fALS and frontotemporal dementia
C. elegans (Karabiyik et al., 2017) and in vitro, depletion leads to due to loss of function or gain of function through three possible
a decrease in the levels of synaptotagmin 11 (SYT11), another mechanisms: (1) haploinsufficiency, (2) repeat-associated non-
PD-associated gene (Bento et al., 2016). Overexpression of AUG (RAN) translations creating toxic dipeptide repeat (DPR)
SYT11 rescues the macroautophagy defects observed in proteins, and (3) sequestration of RNA-binding proteins (RNPs)
ATP13A2-depleted cells, implying that the two proteins lie within through generation of RNA foci involving the C9ORF72 HRE
the same pathway (Wang et al., 2019a). ATP13A2 also recruits RNA (Wen et al., 2017). While the first mechanism results from
the histone deacetylase 6 (HDAC6) to lysosomes to deacetylate loss of function, the latter two mechanisms are considered toxic
a protein implicated in autophagosome-lysosome fusion, cortac- gains of function.
952 Neuron 110, March 16, 2022

ll
Review
Although protein levels of C9ORF72 are reduced by 10%– overexpression of either TDP-43 or C9orf72 (Coyne et al.,
75% in post-mortem tissues, a significant reduction of 2017). Lower levels of HSC70 protein have also been noted in
C9ORF72 expression is not observed in patient-iPSC-derived peripheral blood mononuclear cells from sporadic ALS patients,
MNs (Renton et al., 2011). LC3-II levels are decreased in and silencing of HSC70 in neuroblastoma cell line is sufficient to
C9ALS-patient-iPSC-derived neurons but silencing of precipitate formation of TDP-43 aggregates (Arosio et al., 2020).
C9ORF72 enhances autophagy via inhibition of mTOR activity Although the multiplicity of intracellular functions of HSC70 pre-
and elevation of TFEB levels (Ugolino et al., 2016). C9ORF72 cludes the ability to exclusively attribute these changes in pro-
forms a stable complex with two proteins, the Smith-Magenis teostasis to defective CMA or eMI, these findings should
syndrome chromosome region, candidate 8 (SMCR8), and the generate future interest in exploring the status of both pathways
WD-repeat-containing protein 41 (WDR41). C9ORF72-SMCR8 in ALS.
recruits ULK1 complexes on phagophores in a RAB1A-depen-
dent manner and deficiency of C9ORF72 causes a decrease in THERAPEUTIC STRATEGIES
ULK1 protein, compromising the initiation of autophagy (Pang
and Hu, 2021). The sense repeat RNA of C9ORF72 results in A number of drug-like small molecules and genetic tools upregu-
the accumulation of nuclear and cytoplasmic RNA foci, the latter late macroautophagy and ameliorate pathologies in cellular and
resulting in the formation of stress granules (SG) (Mizielinska animal models of different neurodegenerative diseases (re-
et al., 2013). Wild-type C9ORF72 lowers SGs via autophagic viewed in Lee et al., 2018; Li et al., 2014; Menzies et al., 2017).
degradation by cooperating with P62 (Chitiprolu et al., 2018). Here, we will focus on more recent developments and also
Overall, a reduction of autophagic activity caused by C9ORF72 consider other types of autophagy.
loss of function results in the accumulation of TDP-43, DPR,
and SGs, which would otherwise be eliminated by autophagy. Macroautophagy targeting
The accumulation of TDP-43 is frequently seen in ALS and is L-type Ca2+ channel blockers, such as felodipine, enhance mac-
also mutated in some cases. Knockdown of TDP-43 impacts roautophagy in mouse neurons (Siddiqi et al., 2019). Felodipine
autophagy at multiple steps, such as downregulation of ATG7 has good brain penetration, enhances macroautophagy flux in
and reduction of dynactin subunit 1 expression resulting in an the brain and was found to reduce mutant huntingtin aggregates
overall inhibition of autolysosome formation and impaired auto- a Huntington’s disease (HD) mouse model and ameliorate motor
phagic flux (Xia et al., 2016). Mutations of OPTN and TBK1 phenotypes. Felodipine administered to mimic the plasma con-
observed in ALS patients prevent ubiquitin binding to OPTN centration of humans taking the drug for hypertension, reduced
and OPTN binding to TBK1, respectively, compromising mitoph- levels of insoluble A53T a-synuclein, and ameliorated neurode-
agy (Evans and Holzbaur, 2019). generation and motor phenotypes in a PD mouse model (Siddiqi
Although few studies have investigated the status of other au- et al., 2019).
tophagic pathways in ALS, growing evidence supports possible Lonafarnib, a brain-penetrant farnesyltransferase inhibitor
involvement of CMA failure on ALS disease progression. Inhibi- reduced levels of pathogenic tau and ameliorated brain
tion of CMA results in the accumulation of the truncated form shrinkage and behavioral abnormalities in a tauopathy mouse
of TDP-43 leading to TDP-43 aggregation (Scrivo et al., 2018). model, likely through inhibition of the GTP-binding protein
Furthermore, TDP-43 aggregates (but not overexpressed solu- Rhes (Hernandez et al., 2019).
ble TDP-43) promote transcriptional upregulation of LAMP2A Genetic deletion of the mGluR5 receptor reverses disease pa-
and HSC70, which has been interpreted as a possible early pro- thology in Q111 mHtt knockin mice (HD model) (Ribeiro et al.,
tective mechanism against TPD-43 mediated proteotoxicity. 2014). CTEP, a well-characterized, potent, CNS penetrant
However, as TPD-43 aggregation persists, the associated mGluR5 negative allosteric modulator, facilitated autophagy-
lysosomal damage may likely lead to CMA failure (Scrivo dependent clearance of the huntingtin aggregates and improved
et al., 2018). Interestingly, intrabody-mediated targeting of mis- motor deficits and cognitive impairment in an HD mouse model
folded TDP-43 protein to CMA has proven effective in reducing (Abd-Elrahman and Ferguson, 2019).
TDP-43 aggregates and decreasing neurotoxicity (Tamaki The D2/D3 dopamine receptor (DR) agonist pramipexole pro-
et al., 2018). motes macroautophagy in cell culture by enhancing Beclin 1
CMA has also shown to contribute to degradation of the ubiq- transcription (Wang et al., 2015), and ameliorates disease in
uitin-like protein, ubiquilin-2, which is mutated in forms of ALS the R6/1 HD mouse model where it increased LC3-II and
and ALS-like dementia. Physiological clearance by CMA of ubiq- decreased p62 in the striatum (Luis-Ravelo et al., 2018).
uilin-2, a known regulator of macroautophagy, has been pro- PPARa agonists, gemfibrozil and Wy14643, which induce
posed to contribute to the crosstalk between the two autophagic macroautophagy in cellular models via PPARa, reduce soluble
pathways (Rothenberg et al., 2010). However, expression of amyloid-b levels in the cortex and hippocampus of an AD mouse
mutant UBQLN2P497H in neuronal cells is associated with model, induce macroautophagy, and improve behavioral deficits
reduced expression of LAMP2A in the ventral horn of the spinal (Luo et al., 2020).
cord and its accumulation in ubiquilin-2-positive inclusions Rapid progress has been made developing small molecules
(Chen et al., 2018). such as molecular glues, which stabilize protein-protein interac-
A still poorly explored change in ALS, but with the potential of tions (Schreiber, 2021), and bifunctional molecules, such as pro-
linking this condition with CMA and KFERQ-selective eMI, is the teolysis targeting chimeras (PROTACs) that degrade proteins
sequestration of HSC70 mRNA into inclusions resulting from by forcing their interaction with a ubiquitin E3 ligase that
Neuron 110, March 16, 2022 953

ll
Review
Figure 5. Autophagy tethering compounds (ATTECs) and the autophagy-targeting chimera (AUTAC) system
(A) ATTEC molecules tether the protein of interest to the autophagosomes by direct binding to the protein of interest and to LC3. A proof-of-concept study using
the mutant huntingtin protein (mHTT) demonstrated that these compounds can degrade mHTT both in cells and in vivo in animal models and demonstrated
targeting of mHTT to autophagosomes for subsequent degradation without influencing autophagy activity per se.
(B) AUTAC technology has a similar design to the PROTAC technology and both use ubiquitination to target proteins for degradation. The AUTAC molecule
contains a degradation tag (a guanine derivative called FBnG), which induces K63 polyubiquitination, and a ligand which binds to the target protein to provide
target specificity. The resulting K63 ubiquitination targets the labeled protein for degradation via macroautophagy.
ubiquitinates the target enabling its subsequent proteasomal Clinical trials of autophagy-enhancing drugs for neurodegen-
clearance (Paiva and Crews, 2019). Similar approaches have eration are relatively rare. Much of the effort to date has focused
been developed for macroautophagy. Molecules dubbed auto- on repurposing, and the next phase will likely see the develop-
phagosome-tethering compounds (ATTECs) bind both LC3 ment of specific autophagy-enhancing drugs through focused
and mHTT to target the mutant protein to phagophores for mac- medicinal chemistry on well-validated targets. Such effort within
roautophagic degradation (Li et al., 2019c) (Figure 5). Such AT- the pharmaceutical and biotech sectors should increase the
TECs can lower levels of mutant but not wild-type huntingtin chance of projects progressing from preclinical to clinical
and ameliorate disease in an HD mouse model (Li et al., 2019c). studies.
Chimeric molecules called autophagy-targeting chimeras
(AUTACs) (Takahashi et al., 2019) utilize endogenous tagging Therapeutic targeting through CMA
by S-guanylation of cysteine residues by 8-nitro-cGMP tag The recently described broad role of CMA in neuronal proteosta-
to trigger ubiquitination and then macroautophagic clearance. sis and degradation of pathogenic proteins, and the growing ev-
AUTAC molecules consist of Cys-S-p-fluorobenzylguanine idence of reduced CMA activity in PD, FTD, and AD, has made
(dubbed FBnG), a mimetic of Cys-S-cGMP with improved phys- CMA an attractive target to prevent neuronal proteotoxicity
icochemical properties, attached to a target-specific ligand via a and neurodegeneration.
polyethylene glycol (PEG) linker (Figure 5). The approach was Genetic modulation of CMA in neurodegeneration models has
extended to mitophagy of fragmented mitochondria through primarily focused on LAMP2A. Lentiviral-based LAMP2A over-
the generation of AUTAC4 in which the FBnG is attached to a expression in rats substantia nigra reduced human a-synuclein
warhead binding to the mitochondrial translocator protein aggregation and protected dopaminergic neurons from degen-
(TSPO). AUTAC4 promoted mitophagy, reduced apoptosis, eration (Xilouri et al., 2013).
and maintained levels of intracellular ATP when mitochondrial Since retinoic acid receptor a (RARa) negatively regulates
fragmentation was induced. CMA, activation of this pathway can be attained with retinoic
954 Neuron 110, March 16, 2022

ll
Review
acid derivatives (Anguiano et al., 2013). Extensive medicinal cess may depend on the identification of human biomarkers that
chemistry optimized one of these derivatives (CA77.1), which reflect brain autophagic activities. Dynamic metabolite tracing
improved behavior and tau and Ab-related pathology in FTD (metabolic fluxomics) and multiplex quantitative proteomics
mouse models (Bourdenx et al., 2021). Although interventions including PTMs (Wesseling et al., 2020), and more sensitive
that improve lysosomal function should also indirectly enhance and specific tools for in vivo imaging of human brains for dis-
CMA, this possibility has been rarely investigated. For example, ease-causing autophagic substrates, such as tau, a-synuclein,
lactulose has been proposed to improve Ab pathology through and huntingtin (van Waarde et al., 2021) may help reveal the mo-
macroautophagy and CMA, but CMA activity was not measured lecular signatures of defects in autophagy. Early treatment,
(Lee et al., 2021). Similarly, inhibition of HDAC6 with tubastatin A ideally in presymptomatic individuals, may be necessary, as dis-
was reported to reduce PD-related pathology through CMA acti- ease-protein lowering later in the disease course is not nearly as
vation (Francelle et al., 2020). Although CMA activity was not effective as early removal (Rubinsztein and Orr, 2016). In this
directly measured, the fact that the intervention increased respect, trial strategies and approval processes should evolve
LAMP2A levels justifies future studies. to enable development of preventive agents administered to
PROTAC-like approaches have also been attempted for healthy/presymptomatic people, analogous to the use of statins
CMA. A fusion molecule containing the KFERQ-like motif and in heart disease.
the polyglutamine-binding peptide 1, which interacts with poly- Enhancing autophagosome formation, although effective in
glutamine chains, was effective in targeting mutant huntingtin disease animal models, may have risk in conditions when auto-
for degradation via CMA (Bauer et al., 2010). Intra-striatal deliv- phagosome clearance is defective. This may be resolved by
ery of this fusion molecule reduced pathology in HD models careful in vivo studies aiming to mimic the physiological/disease
and improved the disease phenotype (Bauer et al., 2010). scenario in a model organism. In advanced states of disease,
KFERQ-containing peptides designed to bind Ab oligomers when multiple autophagy steps and pathways may be compro-
and promote degradation through CMA have been effective mised, it would be worth considering combinatorial interventions
(Dou et al., 2020), although this strategy may not involve aiming at restoring flux through multiple autophagic pathways,
CMA, as Ab oligomers are usually extracellular and CMA re- since even partial restoration of each of them may have additive
quires protein unfolding before internalization. It is still possible beneficial effects. The coordinate functioning of autophagy with
that KFERQ-tagging targets instead these proteins to LE/MVB the UPS and chaperones also makes combination of chemical
via eMI. regulators of these components with autophagy-enhancing in-
terventions attractive possibilities.
Conclusions and important future questions Consideration should also be given to the changes on auto-
To maximize our understanding of these areas of biology and in- phagy in aging and the higher probabilities of comorbidities at
crease the probabilities of contributing to therapeutic strategies, advanced ages that may contribute to disease (i.e., diabetes
there are several domains that deserve further exploration. From and AD). Consequently, it will be important to consider the ef-
a basic science perspective, it will be important to appreciate fects of therapeutic agents not only on the neurodegenerative
how different autophagic pathways, the UPS and unconven- disease itself but also on comorbidities and on healthy older
tional secretion communicate and influence each other. One people.
challenge is to devise approaches different from knockout sys- Enhancing autophagic pathways to treat diseases or delay
tems (e.g., ATG-null cells) or pharmacological inhibitors, as these symptom onset has the added benefit that constitutive upregu-
can affect other systems or induce compensatory effects. One lation in animals is generally associated with longevity and other
strategy that may contribute to such analyses is autophagosome health benefits (e.g., Fernández et al., 2018; Pyo et al., 2013).
and lysosomal content proteomic profiling (Le Guerroué et al., Furthermore, the autophagy-inducing agent may not need to
2017; Schneider et al., 2015). engage its target all of the time as with an antihypertensive
We need a better understanding of the roles of autophagic drug but may have efficacy if administered in a pulsatile fashion,
pathways in different glia. This will expand understanding of glial e.g., every few days, which would reduce liabilities of the agent,
physiology and disease relevance, for example, for neuroinflam- increasing the feasibility of this approach.
matory-like. Furthermore, growing evidence of non-cell autono-
mous control of neuronal autophagy by glia that could be utilized ACKNOWLEDGMENTS
as a therapeutic target. For example, chemical enhancement of
CMA in PD astrocytes has proven protective in vitro against This work was supported by UK Dementia Research Institute (funded by
a-synuclein-mediated toxicity in neurons (di Domenico the MRC, Alzheimer’s Research UK and the Alzheimer’s Society), Alz-
heimer’s Research UK (ARUK-2022DDI-CAM, ARUK-TC2020-1, and
et al., 2019). ARUK-PG2018C-001), the Tau Consortium, Cambridge Centre for Parkin-
Further studies testing links between autophagy and psychiat- son-Plus, the National Institutes of Health grants AG054108, AG031782,
ric disease and conditions such as autism will be important for AG021904, and NS100717, and the generous support of the Rainwater
Charitable Foundation, the JPB Foundation, the Backus Foundation, the
understanding their etiologies, therapeutic potential and, by Glenn Foundation, and R&R Belfer and the NIHR Cambridge Biomedical
extension, may also shed light on processes underpinning the Research Centre (BRC-1215-20014). The views expressed are those of
very challenging behavioral features in common neurodegener- the authors and not necessarily those of the NIHR or the Department of
ative diseases. Health and Social Care. A.M.-S. is supported by a Ramon Areces postdoc-
toral fellowship and G.J.K. by a T32 GM007491 and a T32 GM007288. M.B.
Harnessing autophagy-stimulating strategies has real poten- is supported by an ‘‘Allocation Jeune Chercheur’’ from Fondation Alz-
tial for many neurodegenerative diseases, but translational suc- heimer (France).
Neuron 110, March 16, 2022 955

ll
Review
DECLARATION OF INTERESTS Bankston, A.N., Forston, M.D., Howard, R.M., Andres, K.R., Smith, A.E., Ohri,
S.S., Bates, M.L., Bunge, M.B., and Whittemore, S.R. (2019). Autophagy is
essential for oligodendrocyte differentiation, survival, and proper myelination.
D.C.R. is a consultant for Aladdin Healthcare Technologies SE, Drishti Discov-
Glia 67, 1745–1759. https://doi.org/10.1002/glia.23646.
eries, Abbvie, PAQ Therapeutics, MindRank AI, and Nido Biosciences. A.M.C.
is a cofounder and scientific adviser for Life Biosciences, consults for Generian
Bansal, M., Moharir, S.C., Sailasree, S.P., Sirohi, K., Sudhakar, C., Sarathi,
Pharmaceuticals and Cognition Therapeutics, and has US patent US9512092. D.P., Lakshmi, B.J., Buono, M., Kumar, S., and Swarup, G. (2018). Optineurin
promotes autophagosome formation by recruiting the autophagy-related
Atg12-5-16L1 complex to phagophores containing the Wipi2 protein. J. Biol.
REFERENCES Chem. 293, 132–147. https://doi.org/10.1074/jbc.M117.801944.
Abd-Elrahman, K.S., and Ferguson, S.S.G. (2019). Modulation of mTOR and Bauer, P.O., Goswami, A., Wong, H.K., Okuno, M., Kurosawa, M., Yamada,
CREB pathways following mGluR5 blockade contribute to improved Hunting- M., Miyazaki, H., Matsumoto, G., Kino, Y., Nagai, Y., and Nukina, N. (2010).
ton’s pathology in zQ175 mice. Mol. Brain 12, 35. https://doi.org/10.1186/ Harnessing chaperone-mediated autophagy for the selective degradation of
s13041-019-0456-1. mutant huntingtin protein. Nat. Biotechnol. 28, 256–263, nbt.1608.
Aguado, C., Sarkar, S., Korolchuk, V.I., Criado, O., Vernia, S., Boya, P., Sanz, Bejarano, E., Yuste, A., Patel, B., Stout, R.F., Spray, D.C., and Cuervo, A.M.
P., de Córdoba, S.R., Knecht, E., and Rubinsztein, D.C. (2010). Laforin, the (2014). Connexins modulate autophagosome biogenesis. Nat. Cell Biol. 16,
most common protein mutated in Lafora disease, regulates autophagy. 401–414. https://doi.org/10.1038/ncb2934.
Hum. Mol. Genet. 19, 2867–2876. https://doi.org/10.1093/hmg/ddq190.
Bento, C.F., Ashkenazi, A., Jimenez-Sanchez, M., and Rubinsztein, D.C.
Akizu, N., Cantagrel, V., Zaki, M.S., Al-Gazali, L., Wang, X., Rosti, R.O., Diko- (2016). The Parkinson’s disease-associated genes ATP13A2 and SYT11 regu-
glu, E., Gelot, A.B., Rosti, B., Vaux, K.K., et al. (2015). Biallelic mutations in late autophagy via a common pathway. Nat. Commun. 7, 11803. https://doi.
SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autopha- org/10.1038/ncomms11803.
gosome dysfunction. Nat. Genet. 47, 528–534. https://doi.org/10.1038/
ng.3256. Bhaskara, R.M., Grumati, P., Garcia-Pardo, J., Kalayil, S., Covarrubias-Pinto,
A., Chen, W., Kudryashev, M., Dikic, I., and Hummer, G. (2019). Curvature in-
Al Eissa, M.M., Fiorentino, A., Sharp, S.I., O’Brien, N.L., Wolfe, K., Giaroli, G., duction and membrane remodeling by FAM134B reticulon homology domain
Curtis, D., Bass, N.J., and McQuillin, A. (2018). Exome sequence analysis and assist selective ER-phagy. Nat. Commun. 10, 2370. https://doi.org/10.1038/
follow up genotyping implicates rare ULK1 variants to be involved in suscep- s41467-019-10345-3.
tibility to schizophrenia. Ann. Hum. Genet. 82, 88–92. https://doi.org/10.
1111/ahg.12226. Birdsall, V., and Waites, C.L. (2019). Autophagy at the synapse. Neurosci. Lett.
697, 24–28. https://doi.org/10.1016/j.neulet.2018.05.033.
Alessi, D.R., and Sammler, E. (2018). LRRK2 kinase in Parkinson’s disease.
Science 360, 36–37. https://doi.org/10.1126/science.aar5683. Borsche, M., König, I.R., Delcambre, S., Petrucci, S., Balck, A., Bru €ggemann,
N., Zimprich, A., Wasner, K., Pereira, S.L., Avenali, M., et al. (2020). Mitochon-
Anding, A.L., Wang, C., Chang, T.K., Sliter, D.A., Powers, C.M., Hofmann, K., drial damage-associated inflammation highlights biomarkers in PRKN/PINK1
Youle, R.J., and Baehrecke, E.H. (2018). Vps13D encodes a ubiquitin-binding parkinsonism. Brain 143, 3041–3051. https://doi.org/10.1093/brain/awaa246.
protein that is required for the regulation of mitochondrial size and clearance.
Curr. Biol.: CB 28, 287–295. e286. https://doi.org/10.1016/j.cub.2017.11.064. Bourdenx, M., Martı́n-Segura, A., Scrivo, A., Rodriguez-Navarro, J.A.,
Kaushik, S., Tasset, I., Diaz, A., Storm, N.J., Xin, Q., Juste, Y.R., et al.
Anguiano, J., Garner, T.P., Mahalingam, M., Das, B.C., Gavathiotis, E., and (2021). Chaperone-mediated autophagy prevents collapse of the neuronal
Cuervo, A.M. (2013). Chemical modulation of chaperone-mediated autophagy metastable proteome. Cell 184, 2696–2714.e25. https://doi.org/10.1016/j.
by retinoic acid derivatives. Nat. Chem. Biol. 9, 374–382. https://doi.org/10. cell.2021.03.048.
1038/nchembio.1230.
Bryant, D., Liu, Y., Datta, S., Hariri, H., Seda, M., Anderson, G., Peskett, E., De-
Arias, E., and Cuervo, A.M. (2020). Pros and cons of chaperone-mediated
metriou, C., Sousa, S., Jenkins, D., et al. (2018). SNX14 mutations affect endo-
autophagy in cancer biology. Trends Endocrinol. Metab. 31, 53–66. https://
plasmic reticulum-associated neutral lipid metabolism in autosomal recessive
doi.org/10.1016/j.tem.2019.09.007.
spinocerebellar ataxia 20. Hum. Mol. Genet. 27, 1927–1940. https://doi.org/
10.1093/hmg/ddy101.
Arias, E., Koga, H., Diaz, A., Mocholi, E., Patel, B., and Cuervo, A.M. (2015).
Lysosomal mTORC2/PHLPP1/Akt regulate chaperone-mediated autophagy.
Mol. Cell 59, 270–284. https://doi.org/10.1016/j.molcel.2015.05.030. Bu, G.J. (2009). Apolipoprotein E and its receptors in Alzheimer’s disease:
pathways, pathogenesis and therapy. Nat. Rev. Neurosci. 10, 333–344.
https://doi.org/10.1038/nrn2620.
Arosio, A., Cristofani, R., Pansarasa, O., Crippa, V., Riva, C., Sirtori, R., Rodri-
guez-Menendez, V., Riva, N., Gerardi, F., Lunetta, C., et al. (2020). HSC70
expression is reduced in lymphomonocytes of sporadic ALS patients and con- Butzlaff, M., Hannan, S.B., Karsten, P., Lenz, S., Ng, J., Voßfeldt, H., Pru €ßing,
tributes to TDP-43 accumulation. Amyotroph. Lateral Scler. Frontotemporal K., Pflanz, R., Schulz, J.B., Rasse, T., and Voigt, A. (2015). Impaired retrograde
Degener. 21, 51–62. https://doi.org/10.1080/21678421.2019.1672749. transport by the dynein/dynactin complex contributes to Tau-induced toxicity.
Hum. Mol. Genet. 24, 3623–3637. https://doi.org/10.1093/hmg/ddv107.
Ashkenazi, A., Bento, C.F., Ricketts, T., Vicinanza, M., Siddiqi, F., Pavel, M.,
Squitieri, F., Hardenberg, M.C., Imarisio, S., Menzies, F.M., and Rubinsztein, Caballero, B., Bourdenx, M., Luengo, E., Diaz, A., Sohn, P.D., Chen, X., Wang,
D.C. (2017). Polyglutamine tracts regulate autophagy. Autophagy 13, 1613– C., Juste, Y.R., Wegmann, S., Patel, B., et al. (2021). Acetylated tau inhibits
1614. https://doi.org/10.1080/15548627.2017.1336278. chaperone-mediated autophagy and promotes tau pathology propagation in
mice. Nat. Commun. 12, 2238. https://doi.org/10.1038/s41467-021-22501-9.
Axe, E.L., Walker, S.A., Manifava, M., Chandra, P., Roderick, H.L., Haber-
mann, A., Griffiths, G., and Ktistakis, N.T. (2008). Autophagosome formation Caballero, B., Wang, Y.P., Diaz, A., Tasset, I., Juste, Y.R., Stiller, B., Mandel-
from membrane compartments enriched in phosphatidylinositol 3-phosphate kow, E.M., Mandelkow, E., and Cuervo, A.M. (2018). Interplay of pathogenic
and dynamically connected to the endoplasmic reticulum. J. Cell Biol. 182, forms of human tau with different autophagic pathways. Aging Cell 17,
685–701. https://doi.org/10.1083/jcb.200803137. e12692. https://doi.org/10.1111/acel.12692.
Bae, E.J., Yang, N.Y., Lee, C., Lee, H.J., Kim, S., Sardi, S.P., and Lee, S.J. Cenacchi, G., Papa, V., Pegoraro, V., Marozzo, R., Fanin, M., and Angelini, C.
(2015). Loss of glucocerebrosidase 1 activity causes lysosomal dysfunction (2020). Review: danon disease: review of natural history and recent advances.
and a-synuclein aggregation. Exp. Mol. Med. 47, e153. e153. https://doi. Neuropathol. Appl. Neurobiol. 46, 303–322. https://doi.org/10.1111/
org/10.1038/emm.2014.128. nan.12587.
Bandyopadhyay, U., Sridhar, S., Kaushik, S., Kiffin, R., and Cuervo, A.M. Chang, J., Lee, S., and Blackstone, C. (2014). Spastic paraplegia proteins
(2010). Identification of regulators of chaperone-mediated autophagy. Mol. spastizin and spatacsin mediate autophagic lysosome reformation. J. Clin.
Cell 39, 535–547. https://doi.org/10.1016/j.molcel.2010.08.004. Invest. 124, 5249–5262. https://doi.org/10.1172/JCI77598.
956 Neuron 110, March 16, 2022

ll
Review
Chang, J.T., Kumsta, C., Hellman, A.B., Adams, L.M., and Hansen, M. (2017). cellular processes, and emerging therapeutic opportunities. Neurobiol. Dis.
Spatiotemporal regulation of autophagy during Caenorhabditis elegans aging. 122, 83–93. https://doi.org/10.1016/j.nbd.2018.05.012.
eLife 6, 1–23. https://doi.org/10.7554/eLife.18459.
Coyne, A.N., Lorenzini, I., Chou, C.C., Torvund, M., Rogers, R.S., Starr, A.,
Chen, Q., Xiao, Y., Chai, P., Zheng, P., Teng, J., and Chen, J. (2019). ATL3 is a Zaepfel, B.L., Levy, J., Johannesmeyer, J., Schwartz, J.C., et al. (2017).
tubular ER-Phagy receptor for GABARAP-mediated selective autophagy. Post-transcriptional inhibition of Hsc70-4/HSPA8 expression leads to synaptic
Curr. Biol. 29, 846–855.e6. https://doi.org/10.1016/j.cub.2019.01.041. vesicle cycling defects in multiple models of ALS. Cell Rep 21, 110–125.
https://doi.org/10.1016/j.celrep.2017.09.028.
Chen, T., Huang, B., Shi, X., Gao, L., and Huang, C. (2018). Mutant
UBQLN2(P497H) in motor neurons leads to ALS-like phenotypes and defective Cuervo, A.M., and Dice, J.F. (1996). A receptor for the selective uptake and
autophagy in rats. Acta Neuropathol. Commun. 6, 122. https://doi.org/10. degradation of proteins by lysosomes. Science 273, 501–503. https://doi.
1186/s40478-018-0627-9. org/10.1126/science.273.5274.501.
Cheng, J., Liao, Y., Dong, Y., Hu, H., Yang, N., Kong, X., Li, S., Li, X., Guo, J., Cuervo, A.M., Palmer, A., Rivett, A.J., and Knecht, E. (1995). Degradation of
Qin, L., et al. (2020). Microglial autophagy defect causes Parkinson disease- proteasomes by lysosomes in rat liver. Eur. J. Biochem. 227, 792–800.
like symptoms by accelerating inflammasome activation in mice. Autophagy https://doi.org/10.1111/j.1432-1033.1995.tb20203.x.
16, 2193–2205. https://doi.org/10.1080/15548627.2020.1719723.
Cuervo, A.M., Stefanis, L., Fredenburg, R., Lansbury, P.T., and Sulzer, D.
Cherra, S.J., 3rd, Steer, E., Gusdon, A.M., Kiselyov, K., and Chu, C.T. (2013). (2004). Impaired degradation of mutant alpha-synuclein by chaperone-medi-
Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochon- ated autophagy. Science 305, 1292–1295. https://doi.org/10.1126/science.
dria in neurons. Am. J. Pathol. 182, 474–484. https://doi.org/10.1016/j.ajpath. 1101738.
2012.10.027.
Cummins, N., Tweedie, A., Zuryn, S., Bertran-Gonzalez, J., and Götz, J. (2019).
Chiang, H.L., Terlecky, S.R., Plant, C.P., and Dice, J.F. (1989). A role for a 70- Disease-associated tau impairs mitophagy by inhibiting Parkin translocation to
kilodalton heat shock protein in lysosomal degradation of intracellular proteins. mitochondria. EMBO J 38, e99360. https://doi.org/10.15252/embj.
Science 246, 382–385. https://doi.org/10.1126/science.2799391. 201899360.
Chino, H., Hatta, T., Natsume, T., and Mizushima, N. (2019). Intrinsically disor- Dall’Armi, C., Devereaux, K.A., and Di Paolo, G. (2013). The role of lipids in the
dered protein TEX264 mediates ER-phagy. Mol. Cell 74, 909–921.e6. https:// control of autophagy. Curr. Biol. 23, R33–R45. https://doi.org/10.1016/j.cub.
doi.org/10.1016/j.molcel.2019.03.033. 2012.10.041.
Chitiprolu, M., Jagow, C., Tremblay, V., Bondy-Chorney, E., Paris, G., Savard, Davies, A.K., Itzhak, D.N., Edgar, J.R., Archuleta, T.L., Hirst, J., Jackson, L.P.,
A., Palidwor, G., Barry, F.A., Zinman, L., Keith, J., et al. (2018). A complex of Robinson, M.S., and Borner, G.H.H. (2018). AP-4 vesicles contribute to spatial
C9ORF72 and p62 uses arginine methylation to eliminate stress granules by control of autophagy via RUSC-dependent peripheral delivery of ATG9A. Nat.
autophagy. Nat. Commun. 9, 2794. https://doi.org/10.1038/s41467-018- Commun. 9, 3958. https://doi.org/10.1038/s41467-018-06172-7.
05273-7.
Davis, C.H., Kim, K.Y., Bushong, E.A., Mills, E.A., Boassa, D., Shih, T., Kinebu-
Cho, M.H., Cho, K., Kang, H.J., Jeon, E.Y., Kim, H.S., Kwon, H.J., Kim, H.M., chi, M., Phan, S., Zhou, Y., Bihlmeyer, N.A., et al. (2014). Transcellular degra-
Kim, D.H., and Yoon, S.Y. (2014). Autophagy in microglia degrades extracel- dation of axonal mitochondria. Proc. Natl. Acad. Sci. USA 111, 9633–9638.
lular beta-amyloid fibrils and regulates the NLRP3 inflammasome. Autophagy https://doi.org/10.1073/pnas.1404651111.
10, 1761–1775. https://doi.org/10.4161/auto.29647.
Decressac, M., Mattsson, B., Weikop, P., Lundblad, M., Jakobsson, J., and
Choi, I., Zhang, Y., Seegobin, S.P., Pruvost, M., Wang, Q., Purtell, K., Zhang, Björklund, A. (2013). TFEB-mediated autophagy rescues midbrain dopamine
B., and Yue, Z. (2020). Microglia clear neuron-released alpha-synuclein via se- neurons from a-synuclein toxicity. Proc. Natl. Acad. Sci. USA 110, E1817–
lective autophagy and prevent neurodegeneration. Nat. Commun. 11, 1386. E1826. https://doi.org/10.1073/pnas.1305623110.
https://doi.org/10.1038/s41467-020-15119-w.
Degterev, A., Ofengeim, D., and Yuan, J. (2019). Targeting RIPK1 for the treat-
Chong, C.M., Ke, M., Tan, Y., Huang, Z., Zhang, K., Ai, N., Ge, W., Qin, D., Lu, ment of human diseases. Proc. Natl. Acad. Sci. USA 116, 9714–9722. https://
J.H., and Su, H. (2018). Presenilin 1 deficiency suppresses autophagy in hu- doi.org/10.1073/pnas.1901179116.
man neural stem cells through reducing gamma-secretase-independent
ERK/CREB signaling. Cell Death Dis 9, 879. https://doi.org/10.1038/s41419- Dehay, B., Ramirez, A., Martinez-Vicente, M., Perier, C., Canron, M.H., Doud-
018-0945-7. nikoff, E., Vital, A., Vila, M., Klein, C., and Bezard, E. (2012). Loss of P-type
ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and
Choubey, V., Safiulina, D., Vaarmann, A., Cagalinec, M., Wareski, P., Kuum, leads to Parkinson disease neurodegeneration. Proc. Natl. Acad. Sci. USA
M., Zharkovsky, A., and Kaasik, A. (2011). Mutant A53T a-synuclein induces 109, 9611–9616. https://doi.org/10.1073/pnas.1112368109.
neuronal death by increasing mitochondrial autophagy. J. Biol. Chem. 286,
10814–10824. https://doi.org/10.1074/jbc.M110.132514. Deng, Z., Purtell, K., Lachance, V., Wold, M.S., Chen, S., and Yue, Z. (2017).
Autophagy receptors and neurodegenerative diseases. Trends Cell Biol 27,
Chung, Y., Lee, J., Jung, S., Lee, Y., Cho, J.W., and Oh, Y.J. (2018). Dysregu- 491–504. https://doi.org/10.1016/j.tcb.2017.01.001.
lated autophagy contributes to caspase-dependent neuronal apoptosis. Cell
Death Dis 9, 1189. https://doi.org/10.1038/s41419-018-1229-y. di Domenico, A., Carola, G., Calatayud, C., Pons-Espinal, M., Muñoz, J.P., Ri-
chaud-Patin, Y., Fernandez-Carasa, I., Gut, M., Faella, A., Parameswaran, J.,
Cohen-Kaplan, V., Livneh, I., Avni, N., Fabre, B., Ziv, T., Kwon, Y.T., and Cie- et al. (2019). Patient-specific iPSC-derived astrocytes contribute to non-cell-
chanover, A. (2016). p62- and ubiquitin-dependent stress-induced autophagy autonomous neurodegeneration in Parkinson’s disease. Stem Cell Rep 12,
of the mammalian 26S proteasome. Proc. Natl. Acad. Sci. USA 113, E7490– 213–229. https://doi.org/10.1016/j.stemcr.2018.12.011.
E7499. https://doi.org/10.1073/pnas.1615455113.
Dibble, C.C., and Manning, B.D. (2013). Signal integration by mTORC1 coor-
Collier, J.J., Guissart, C., Oláhová, M., Sasorith, S., Piron-Prunier, F., Suomi, dinates nutrient input with biosynthetic output. Nat. Cell Biol. 15, 555–564.
F., Zhang, D., Martinez-Lopez, N., Leboucq, N., Bahr, A., et al. (2021). Devel- https://doi.org/10.1038/ncb2763.
opmental consequences of defective ATG7-mediated autophagy in humans.
N. Engl. J. Med. 384, 2406–2417. https://doi.org/10.1056/NEJMoa1915722. Domise, M., Sauvé, F., Didier, S., Caillerez, R., Bégard, S., Carrier, S., Colin,
M., Marinangeli, C., Buée, L., and Vingtdeux, V. (2019). Neuronal AMP-acti-
Compans, B., Camus, C., Kallergi, E., Sposini, S., Martineau, M., Butler, C., vated protein kinase hyper-activation induces synaptic loss by an auto-
Kechkar, A., Klaassen, R.V., Retailleau, N., Sejnowski, T.J., et al. (2021). phagy-mediated process. Cell Death Dis 10, 221. https://doi.org/10.1038/
NMDAR-dependent long-term depression is associated with increased short s41419-019-1464-x.
term plasticity through autophagy mediated loss of PSD-95. Nat. Commun.
12, 2849. https://doi.org/10.1038/s41467-021-23133-9. Dong, S., Aguirre-Hernandez, C., Scrivo, A., Eliscovich, C., Arias, E., Bravo-
Cordero, J.J., and Cuervo, A.M. (2020). Monitoring spatiotemporal changes
Cortes, C.J., and La Spada, A.R. (2019). TFEB dysregulation as a driver of in chaperone-mediated autophagy in vivo. Nat. Commun. 11, 645. https://
autophagy dysfunction in neurodegenerative disease: molecular mechanisms, doi.org/10.1038/s41467-019-14164-4.
Neuron 110, March 16, 2022 957

ll
Review
Dong, S., Wang, Q., Kao, Y.R., Diaz, A., Tasset, I., Kaushik, S., Thiruthuvana- SOD1 to LC3 via an ubiquitin-independent mechanism. J. Neurochem. 111,
than, V., Zintiridou, A., Nieves, E., Dzieciatkowska, M., et al. (2021). Chap- 1062–1073. https://doi.org/10.1111/j.1471-4159.2009.06388.x.
erone-mediated autophagy sustains haematopoietic stem-cell function. Na-
ture 591, 117–123. https://doi.org/10.1038/s41586-020-03129-z. Galluzzi, L., and Green, D.R. (2019). Autophagy-independent functions of the
autophagy machinery. Cell 177, 1682–1699. https://doi.org/10.1016/j.cell.
Dou, J., Su, P., Xu, C., Wen, Z., Mao, Z., and Li, W. (2020). Targeting Hsc70- 2019.05.026.
based autophagy to eliminate amyloid beta oligomers. Biochem. Biophys.
Res. Commun. 524, 923–928. https://doi.org/10.1016/j.bbrc.2020.02.016. Ganley, I.G., Wong, P.M., Gammoh, N., and Jiang, X. (2011). Distinct autopha-
gosomal-lysosomal fusion mechanism revealed by thapsigargin-induced
Eapen, V.V., Swarup, S., Hoyer, M.J., Paulo, J.A., and Harper, J.W. (2021). autophagy arrest. Mol. Cell 42, 731–743. https://doi.org/10.1016/j.molcel.
Quantitative proteomics reveals the selectivity of ubiquitin-binding autophagy 2011.04.024.
receptors in the turnover of damaged lysosomes by lysophagy. eLife 10,
e72328. https://doi.org/10.7554/eLife.72328. €kinen, V.P. (2018). Genetic varia-
Gao, S., Casey, A.E., Sargeant, T.J., and Ma
tion within endolysosomal system is associated with late-onset Alzheimer’s
Ehlers, M.D. (2000). Reinsertion or degradation of AMPA receptors determined disease. Brain 141, 2711–2720. https://doi.org/10.1093/brain/awy197.
by activity-dependent endocytic sorting. Neuron 28, 511–525. https://doi.org/
10.1016/s0896-6273(00)00129-x. Gascón, S., Murenu, E., Masserdotti, G., Ortega, F., Russo, G.L., Petrik, D.,
Deshpande, A., Heinrich, C., Karow, M., Robertson, S.P., et al. (2016). Identi-
Elia, L.P., Mason, A.R., Alijagic, A., and Finkbeiner, S. (2019). Genetic regula- fication and successful negotiation of a metabolic checkpoint in direct
tion of neuronal progranulin reveals a critical role for the autophagy-lysosome neuronal reprogramming. Cell Stem Cell 18, 396–409. https://doi.org/10.
pathway. J. Neurosci. 39, 3332–3344. https://doi.org/10.1523/JNEUROSCI. 1016/j.stem.2015.12.003.
3498-17.2019.
Gassen, N.C., Hartmann, J., Zschocke, J., Stepan, J., Hafner, K., Zellner, A.,
Endicott, S.J., Ziemba, Z.J., Beckmann, L.J., Boynton, D.N., and Miller, R.A. Kirmeier, T., Kollmannsberger, L., Wagner, K.V., Dedic, N., et al. (2014). Asso-
(2020). Inhibition of class I PI3K enhances chaperone-mediated autophagy. ciation of FKBP51 with priming of autophagy pathways and mediation of anti-
J. Cell Biol. 219. https://doi.org/10.1083/jcb.202001031. depressant treatment response: evidence in cells, mice, and humans. PLoS
Med 11, e1001755. https://doi.org/10.1371/journal.pmed.1001755.
Evans, C.S., and Holzbaur, E.L.F. (2019). Autophagy and mitophagy in ALS.
Neurobiol. Dis. 122, 35–40. https://doi.org/10.1016/j.nbd.2018.07.005. Gassen, N.C., and Rein, T. (2019). Is there a role of autophagy in depression
and antidepressant action? Front. Psychiatry 10, 337. https://doi.org/10.
Evans, C.S., and Holzbaur, E.L.F. (2020). Quality control in neurons: mitophagy 3389/fpsyt.2019.00337.
and other selective autophagy mechanisms. J. Mol. Biol. 432, 240–260.
https://doi.org/10.1016/j.jmb.2019.06.031. Ge, L., and Schekman, R. (2014). The ER-Golgi intermediate compartment
feeds the phagophore membrane. Autophagy 10, 170–172. https://doi.org/
Fang, E.F., Hou, Y.J., Palikaras, K., Adriaanse, B.A., Kerr, J.S., Yang, B.M., 10.4161/auto.26787.
Lautrup, S., Hasan-Olive, M.M., Caponio, D., Dan, X.L., et al. (2019). Mitoph-
agy inhibits amyloid-beta and tau pathology and reverses cognitive deficits Ge, P., Dawson, V.L., and Dawson, T.M. (2020). PINK1 and Parkin mitochon-
in models of Alzheimer’s disease. Nat. Neurosci. 22, 401–412+. https://doi. drial quality control: a source of regional vulnerability in Parkinson’s disease.
org/10.1038/s41593-018-0332-9. Mol. Neurodegener. 15, 20. https://doi.org/10.1186/s13024-020-00367-7.
Farg, M.A., Sundaramoorthy, V., Sultana, J.M., Yang, S., Atkinson, R.A.K., Geisler, S., Holmström, K.M., Skujat, D., Fiesel, F.C., Rothfuss, O.C., Kahle,
Levina, V., Halloran, M.A., Gleeson, P.A., Blair, I.P., Soo, K.Y., et al. (2014). P.J., and Springer, W. (2010). PINK1/Parkin-mediated mitophagy is depen-
C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal de- dent on VDAC1 and p62/SQSTM1. Nat. Cell Biol. 12, 119–131. https://doi.
mentia, regulates endosomal trafficking. Hum. Mol. Genet. 23, 3579–3595. org/10.1038/ncb2012.
https://doi.org/10.1093/hmg/ddu068.
Glatigny, M., Moriceau, S., Rivagorda, M., Ramos-Brossier, M., Nascimbeni,
Ferguson, C.J., Lenk, G.M., and Meisler, M.H. (2009). Defective autophagy in A.C., Lante, F., Shanley, M.R., Boudarene, N., Rousseaud, A., Friedman,
neurons and astrocytes from mice deficient in PI(3,5)P2. Hum. Mol. Genet. 18, A.K., et al. (2019). Autophagy is required for memory formation and reverses
4868–4878. https://doi.org/10.1093/hmg/ddp460. age-related memory decline. Curr. Biol.: CB 29, 435–448. e438. https://doi.
org/10.1016/j.cub.2018.12.021.
Fernández, Á.F., Sebti, S., Wei, Y., Zou, Z., Shi, M., McMillan, K.L., He, C.,
Ting, T., Liu, Y., Chiang, W.C., et al. (2018). Disruption of the beclin 1-BCL2 Goodall, M.L., Fitzwalter, B.E., Zahedi, S., Wu, M., Rodriguez, D., Mulcahy-
autophagy regulatory complex promotes longevity in mice. Nature 558, Levy, J.M., Green, D.R., Morgan, M., Cramer, S.D., and Thorburn, A. (2016).
136–140. https://doi.org/10.1038/s41586-018-0162-7. The autophagy machinery controls cell death switching between apoptosis
and necroptosis. Dev. Cell 37, 337–349. https://doi.org/10.1016/j.devcel.
Filimonenko, M., Stuffers, S., Raiborg, C., Yamamoto, A., Malerød, L., Fisher, 2016.04.018.
E.M., Isaacs, A., Brech, A., Stenmark, H., and Simonsen, A. (2007). Functional
multivesicular bodies are required for autophagic clearance of protein aggre- Goode, A., Butler, K., Long, J., Cavey, J., Scott, D., Shaw, B., Sollenberger, J.,
gates associated with neurodegenerative disease. J. Cell Biol. 179, 485–500. Gell, C., Johansen, T., Oldham, N.J., et al. (2016). Defective recognition of
https://doi.org/10.1083/jcb.200702115. LC3B by mutant SQSTM1/p62 implicates impairment of autophagy as a path-
ogenic mechanism in ALS-FTLD. Autophagy 12, 1094–1104. https://doi.org/
Fleming, A., and Rubinsztein, D.C. (2020). Autophagy in neuronal development 10.1080/15548627.2016.1170257.
and plasticity. Trends Neurosci 43, 767–779. https://doi.org/10.1016/j.tins.
2020.07.003. Grumati, P., Morozzi, G., Hölper, S., Mari, M., Harwardt, M.I., Yan, R., Mu€ller,
S., Reggiori, F., Heilemann, M., and Dikic, I. (2017). Full length RTN3 regulates
Francelle, L., Outeiro, T.F., and Rappold, G.A. (2020). Inhibition of HDAC6 ac- turnover of tubular endoplasmic reticulum via selective autophagy. Elife 6,
tivity protects dopaminergic neurons from alpha-synuclein toxicity. Sci. Rep. e25555. https://doi.org/10.7554/eLife.25555.
10, 6064. https://doi.org/10.1038/s41598-020-62678-5.
Hansen, M., Chandra, A., Mitic, L.L., Onken, B., Driscoll, M., and Kenyon, C.
Fricker, M., Tolkovsky, A.M., Borutaite, V., Coleman, M., and Brown, G.C. (2008). A role for autophagy in the extension of lifespan by dietary restriction
(2018). Neuronal cell death. Physiol. Rev. 98, 813–880. https://doi.org/10. in C. elegans. PLoS Genet 4, e24. https://doi.org/10.1371/journal.pgen.
1152/physrev.00011.2017. 0040024.
Fumagalli, F., Noack, J., Bergmann, T.J., Cebollero, E., Pisoni, G.B., Fasana, Hansen, M., Rubinsztein, D.C., and Walker, D.W. (2018). Autophagy as a pro-
E., Fregno, I., Galli, C., Loi, M., Soldà, T., et al. (2016). Translocon component moter of longevity: insights from model organisms. Nat. Rev. Mol. Cell Biol. 19,
Sec62 acts in endoplasmic reticulum turnover during stress recovery. Nat. Cell 579–593. https://doi.org/10.1038/s41580-018-0033-y.
Biol. 18, 1173–1184. https://doi.org/10.1038/ncb3423.
He, S., Zeng, D., Xu, F., Zhang, J., Zhao, N., Wang, Q., Shi, J., Lin, Z., Yu, W.,
Gal, J., Ström, A.L., Kwinter, D.M., Kilty, R., Zhang, J., Shi, P., Fu, W., Wooten, and Li, H. (2019). Baseline serum levels of beclin-1, but not inflammatory fac-
M.W., and Zhu, H. (2009). Sequestosome 1/p62 links familial ALS mutant tors, may predict antidepressant treatment response in Chinese Han patients
958 Neuron 110, March 16, 2022

ll
Review
with MDD: a preliminary study. Front. Psychiatry 10, 378. https://doi.org/10. Jelani, M., Dooley, H.C., Gubas, A., Mohamoud, H.S.A., Khan, M.T.M., Ali, Z.,
3389/fpsyt.2019.00378. Kang, C., Rahim, F., Jan, A., Vadgama, N., et al. (2019). A mutation in the major
autophagy gene, WIPI2, associated with global developmental abnormalities.
Heckmann, B.L., Boada-Romero, E., Cunha, L.D., Magne, J., and Green, D.R. Brain 142, 1242–1254. https://doi.org/10.1093/brain/awz075.
(2017). LC3-associated phagocytosis and inflammation. J. Mol. Biol. 429,
3561–3576. https://doi.org/10.1016/j.jmb.2017.08.012. Ji, C., Zhao, H., Chen, D., Zhang, H., and Zhao, Y.G. (2021). b-propeller pro-
teins WDR45 and WDR45B regulate autophagosome maturation into autoly-
Heckmann, B.L., Teubner, B.J.W., Tummers, B., Boada-Romero, E., Harris, L., sosomes in neural cells. Curr. Biol. 31, 1666–1677.e6. https://doi.org/10.
Yang, M., Guy, C.S., Zakharenko, S.S., and Green, D.R. (2019). LC3-associ- 1016/j.cub.2021.01.081.
ated endocytosis facilitates beta-amyloid clearance and mitigates neurode-
generation in murine Alzheimer’s disease. Cell 178, 536–551.e14. https://doi. Jo, D.S., Park, N.Y., and Cho, D.H. (2020). Peroxisome quality control and dys-
org/10.1016/j.cell.2019.05.056. regulated lipid metabolism in neurodegenerative diseases. Exp. Mol. Med. 52,
1486–1495. https://doi.org/10.1038/s12276-020-00503-9.
Henry, A.G., Aghamohammadzadeh, S., Samaroo, H., Chen, Y., Mou, K., Nee-
dle, E., and Hirst, W.D. (2015). Pathogenic LRRK2 mutations, through Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P.V., Snae-
increased kinase activity, produce enlarged lysosomes with reduced degrada- dal, J., Bjornsson, S., Huttenlocher, J., Levey, A.I., Lah, J.J., et al. (2013).
tive capacity and increase ATP13A2 expression. Hum. Mol. Genet. 24, 6013– Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J.
6028. https://doi.org/10.1093/hmg/ddv314. Med. 368, 107–116. https://doi.org/10.1056/NEJMoa1211103.
Hernandez, D., Torres, C.A., Setlik, W., Cebrián, C., Mosharov, E.V., Tang, G., Ju, J.S., Fuentealba, R.A., Miller, S.E., Jackson, E., Piwnica-Worms, D., Baloh,
Cheng, H.C., Kholodilov, N., Yarygina, O., Burke, R.E., et al. (2012). Regulation R.H., and Weihl, C.C. (2009). Valosin-containing protein (VCP) is required for
of presynaptic neurotransmission by macroautophagy. Neuron 74, 277–284. autophagy and is disrupted in VCP disease. J. Cell Biol. 187, 875–888.
https://doi.org/10.1016/j.neuron.2012.02.020. https://doi.org/10.1083/jcb.200908115.
Hernandez, I., Luna, G., Rauch, J.N., Reis, S.A., Giroux, M., Karch, C.M., Boc- Juste, Y.R., Kaushik, S., Bourdenx, M., Aflakpui, R., Bandyopadhyay, S., Gar-
tor, D., Sibih, Y.E., Storm, N.J., Diaz, A., et al. (2019). A farnesyltransferase in- cia, F., Diaz, A., Lindenau, K., Tu, V., Krause, G.J., et al. (2021). Reciprocal
hibitor activates lysosomes and reduces tau pathology in mice with tauopathy. regulation of chaperone-mediated autophagy and the circadian clock. Nat.
Sci. Transl. Med. 11. eaat3005. https://doi.org/10.1126/scitranslmed.aat3005. Cell Biol. 23, 1255–1270.
Hill, S.M., Wrobel, L., Ashkenazi, A., Fernandez-Estevez, M., Tan, K., Bu€rli, Kabuta, T., Furuta, A., Aoki, S., Furuta, K., and Wada, K. (2008). Aberrant inter-
R.W., and Rubinsztein, D.C. (2021). VCP/p97 regulates Beclin-1-dependent action between Parkinson disease-associated mutant UCH-L1 and the lyso-
autophagy initiation. Nat. Chem. Biol. 17, 448–455. https://doi.org/10.1038/ somal receptor for chaperone-mediated autophagy. J. Biol. Chem. 283,
s41589-020-00726-x. 23731–23738. https://doi.org/10.1074/jbc.M801918200.
Hoeffer, C.A., Sanchez, E., Hagerman, R.J., Mu, Y., Nguyen, D.V., Wong, H., Kara, N.Z., Flaisher-Grinberg, S., Anderson, G.W., Agam, G., and Einat, H.
Whelan, A.M., Zukin, R.S., Klann, E., and Tassone, F. (2012). Altered mTOR (2018). Mood-stabilizing effects of rapamycin and its analog temsirolimus:
signaling and enhanced CYFIP2 expression levels in subjects with fragile X relevance to autophagy. Behav. Pharmacol. 29, 379–384. https://doi.org/10.
syndrome. Genes Brain Behav 11, 332–341. https://doi.org/10.1111/j.1601- 1097/FBP.0000000000000334.
183X.2012.00768.x.
Kara, N.Z., Toker, L., Agam, G., Anderson, G.W., Belmaker, R.H., and Einat, H.
Holth, J.K., Fritschi, S.K., Wang, C., Pedersen, N.P., Cirrito, J.R., Mahan, T.E., (2013). Trehalose induced antidepressant-like effects and autophagy
Finn, M.B., Manis, M., Geerling, J.C., Fuller, P.M., et al. (2019). The sleep-wake enhancement in mice. Psychopharmacol. (Berl.) 229, 367–375. https://doi.
cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Sci- org/10.1007/s00213-013-3119-4.
ence 363, 880–884. https://doi.org/10.1126/science.aav2546.
Karabiyik, C., Lee, M.J., and Rubinsztein, D.C. (2017). Autophagy impairment
Honda, S., Arakawa, S., Yamaguchi, H., Torii, S., Tajima Sakurai, H., Tsujioka, in Parkinson’s disease. Essays Biochem 61, 711–720. https://doi.org/10.1042/
M., Murohashi, M., and Shimizu, S. (2020). Association between Atg5-inde- EBC20170023.
pendent alternative autophagy and neurodegenerative diseases. J. Mol.
Biol. 432, 2622–2632. https://doi.org/10.1016/j.jmb.2020.01.016. Karabiyik, C., Vicinanza, M., Son, S.M., and Rubinsztein, D.C. (2021). Glucose
starvation induces autophagy via ULK1-mediated activation of PIKfyve in an
Hosokawa, N., Hara, T., Kaizuka, T., Kishi, C., Takamura, A., Miura, Y., Iemura, AMPK-dependent manner. Dev. Cell 56, 1961–1975.e5. https://doi.org/10.
S., Natsume, T., Takehana, K., Yamada, N., et al. (2009). Nutrient-dependent 1016/j.devcel.2021.05.010.
mTORC1 association with the ULK1-Atg13-FIP200 complex required for auto-
phagy. Mol. Biol. Cell 20, 1981–1991. https://doi.org/10.1091/mbc.E08- Kaushik, S., Arias, E., Kwon, H., Lopez, N.M., Athonvarangkul, D., Sahu, S.,
12-1248. Schwartz, G.J., Pessin, J.E., and Singh, R. (2012). Loss of autophagy in hypo-
thalamic POMC neurons impairs lipolysis. EMBO Rep 13, 258–265. https://doi.
Houtman, J., Freitag, K., Gimber, N., Schmoranzer, J., Heppner, F.L., and Jen- org/10.1038/embor.2011.260.
drach, M. (2019). Beclin1-driven autophagy modulates the inflammatory
response of microglia via NLRP3. EMBO J 38, e99430. https://doi.org/10. Kaushik, S., and Cuervo, A.M. (2018). The coming of age of chaperone-medi-
15252/embj.201899430. ated autophagy. Nat. Rev. Mol. Cell Biol. 19, 365–381. https://doi.org/10.1038/
s41580-018-0001-6.
Hung, C., Tuck, E., Stubbs, V., van der Lee, S.J., Aalfs, C., van Spaendonk, R.,
Scheltens, P., Hardy, J., Holstege, H., and Livesey, F.J. (2021). SORL1 defi- Kaushik, S., Tasset, I., Arias, E., Pampliega, O., Wong, E., Martinez-Vicente,
ciency in human excitatory neurons causes APP-dependent defects in the en- M., and Cuervo, A.M. (2021). Autophagy and the hallmarks of aging. Ageing
dolysosome-autophagy network. Cell Rep 35, 109259. https://doi.org/10. Res. Rev. 72, 101468. https://doi.org/10.1016/j.arr.2021.101468.
1016/j.celrep.2021.109259.
Khaminets, A., Heinrich, T., Mari, M., Grumati, P., Huebner, A.K., Akutsu, M.,
Jacomin, A.C., Gohel, R., Hussain, Z., Varga, A., Maruzs, T., Eddison, M., Sica, Liebmann, L., Stolz, A., Nietzsche, S., Koch, N., et al. (2015). Regulation of
M., Jain, A., Moffat, K.G., Johansen, T., et al. (2021). Degradation of arouser by endoplasmic reticulum turnover by selective autophagy. Nature 522,
endosomal microautophagy is essential for adaptation to starvation in 354–358. https://doi.org/10.1038/nature14498.
Drosophila. Life Sci. Alliance 4, 4. https://doi.org/10.26508/lsa.202000965.
Kim, H.J., Cho, M.H., Shim, W.H., Kim, J.K., Jeon, E.Y., Kim, D.H., and Yoon,
€nen, S.B., Chaachouay, H., and Richter-Landsberg, C. (2010). Autophagy is
Ja S.Y. (2017). Deficient autophagy in microglia impairs synaptic pruning and
activated by proteasomal inhibition and involved in aggresome clearance in causes social behavioral defects. Mol. Psychiatry 22, 1576–1584. https://
cultured astrocytes. Glia 58, 1766–1774. https://doi.org/10.1002/glia.21047. doi.org/10.1038/mp.2016.103.
Jang, S.Y., Shin, Y.K., Park, S.Y., Park, J.Y., Rha, S.H., Kim, J.K., Lee, H.J., Kim, M., Sandford, E., Gatica, D., Qiu, Y., Liu, X., Zheng, Y., Schulman, B.A.,
and Park, H.T. (2015). Autophagy is involved in the reduction of myelinating Xu, J., Semple, I., Ro, S.H., et al. (2016). Mutation in ATG5 reduces autophagy
Schwann cell cytoplasm during myelin maturation of the peripheral nerve. and leads to ataxia with developmental delay. eLife 5, e12245. https://doi.org/
PLoS One 10, e0116624. https://doi.org/10.1371/journal.pone.0116624. 10.7554/eLife.12245.
Neuron 110, March 16, 2022 959

ll
Review
Kirchner, P., Bourdenx, M., Madrigal-Matute, J., Tiano, S., Diaz, A., Bartholdy, Li, C., Wang, X., Li, X., Qiu, K., Jiao, F., Liu, Y., Kong, Q., Liu, Y., and Wu, Y.
B.A., Will, B., and Cuervo, A.M. (2019). Proteome-wide analysis of chaperone- (2019a). Proteasome inhibition activates autophagy-lysosome pathway asso-
mediated autophagy targeting motifs. PLOS Biol 17, e3000301. https://doi. ciated with TFEB dephosphorylation and nuclear translocation. Front. Cell
org/10.1371/journal.pbio.3000301. Dev. Biol. 7, 170. https://doi.org/10.3389/fcell.2019.00170.
Komander, D., and Rape, M. (2012). The ubiquitin code. Annu. Rev. Biochem. Li, H., Ham, A., Ma, T.C., Kuo, S.H., Kanter, E., Kim, D., Ko, H.S., Quan, Y.,
81, 203–229. https://doi.org/10.1146/annurev-biochem-060310-170328. Sardi, S.P., Li, A., et al. (2019b). Mitochondrial dysfunction and mitophagy
defect triggered by heterozygous GBA mutations. Autophagy 15, 113–130.
Kononenko, N.L., Claßen, G.A., Kuijpers, M., Puchkov, D., Maritzen, T., https://doi.org/10.1080/15548627.2018.1509818.
Tempes, A., Malik, A.R., Skalecka, A., Bera, S., Jaworski, J., and Haucke, V.
(2017). Retrograde transport of TrkB-containing autophagosomes via the Li, J., Kim, S.G., and Blenis, J. (2014). Rapamycin: one drug, many effects. Cell
adaptor AP-2 mediates neuronal complexity and prevents neurodegeneration. Metab 19, 373–379. https://doi.org/10.1016/j.cmet.2014.01.001.
Nat. Commun. 8, 14819. https://doi.org/10.1038/ncomms14819.
Li, Z., Wang, C., Wang, Z., Zhu, C., Li, J., Sha, T., Ma, L., Gao, C., Yang, Y.,
Korolchuk, V.I., Mansilla, A., Menzies, F.M., and Rubinsztein, D.C. (2009). Sun, Y., et al. (2019c). Allele-selective lowering of mutant HTT protein by
Autophagy inhibition compromises degradation of ubiquitin-proteasome HTT-LC3 linker compounds. Nature 575, 203–209. https://doi.org/10.1038/
pathway substrates. Mol. Cell 33, 517–527. https://doi.org/10.1016/j.molcel. s41586-019-1722-1.
2009.01.021.
Liang, C.C., Wang, C., Peng, X., Gan, B., and Guan, J.L. (2010). Neural-spe-
Krajewska, M., You, Z., Rong, J., Kress, C., Huang, X., Yang, J., Kyoda, T.,
cific deletion of FIP200 leads to cerebellar degeneration caused by increased
Leyva, R., Banares, S., Hu, Y., et al. (2011). Neuronal deletion of caspase 8 pro-
neuronal death and axon degeneration. J. Biol. Chem. 285, 3499–3509.
tects against brain injury in mouse models of controlled cortical impact and
https://doi.org/10.1074/jbc.M109.072389.
kainic acid-induced excitotoxicity. PLoS One 6, e24341. https://doi.org/10.
1371/journal.pone.0024341.
Liang, J.R., Lingeman, E., Ahmed, S., and Corn, J.E. (2018). Atlastins remodel
Krause, G.J., and Cuervo, A.M. (2021). Assessment of mammalian endosomal the endoplasmic reticulum for selective autophagy. J. Cell Biol. 217, 3354–
microautophagy. Methods Cell Biol 164, 167–185. https://doi.org/10.1016/bs. 3367. https://doi.org/10.1083/jcb.201804185.
mcb.2020.10.009.
Lieberman, O.J., and Sulzer, D. (2020). The synaptic autophagy cycle. J. Mol.
Kuijpers, M., Kochlamazashvili, G., Stumpf, A., Puchkov, D., Swaminathan, A., Biol. 432, 2589–2604. https://doi.org/10.1016/j.jmb.2019.12.028.
Lucht, M.T., Krause, E., Maritzen, T., Schmitz, D., and Haucke, V. (2021).
Neuronal autophagy regulates presynaptic neurotransmission by controlling Lipinski, M.M., Zheng, B., Lu, T., Yan, Z., Py, B.F., Ng, A., Xavier, R.J., Li, C.,
the axonal endoplasmic reticulum. Neuron 109, 299–313.e9. https://doi.org/ Yankner, B.A., Scherzer, C.R., and Yuan, J. (2010). Genome-wide analysis re-
10.1016/j.neuron.2020.10.005. veals mechanisms modulating autophagy in normal brain aging and in Alz-
heimer’s disease. Proc. Natl. Acad. Sci. USA 107, 14164–14169. https://doi.
Kulkarni, V.V., and Maday, S. (2018). Compartment-specific dynamics and org/10.1073/pnas.1009485107.
functions of autophagy in neurons. Dev. Neurobiol. 78, 298–310. https://doi.
org/10.1002/dneu.22562. Liu, H., Dai, C., Fan, Y., Guo, B., Ren, K., Sun, T., and Wang, W. (2017). From
autophagy to mitophagy: the roles of P62 in neurodegenerative diseases.
Lachance, V., Wang, Q., Sweet, E., Choi, I., Cai, C.Z., Zhuang, X.X., Zhang, Y., J. Bioenerg. Biomembr. 49, 413–422. https://doi.org/10.1007/s10863-017-
Jiang, J.L., Blitzer, R.D., Bozdagi-Gunal, O., et al. (2019). Autophagy protein 9727-7.
NRBF2 has reduced expression in Alzheimer’s brains and modulates memory
and amyloid-beta homeostasis in mice. Mol. Neurodegener. 14, 43. https:// Liu, N., Zhao, H., Zhao, Y.G., Hu, J., and Zhang, H. (2021). Atlastin 2/3 regulate
doi.org/10.1186/s13024-019-0342-4. ER targeting of the ULK1 complex to initiate autophagy. J. Cell Biol. 220.
https://doi.org/10.1083/jcb.202012091.
Lauritzen, I., Pardossi-Piquard, R., Bourgeois, A., Pagnotta, S., Biferi, M.G.,
Barkats, M., Lacor, P., Klein, W., Bauer, C., and Checler, F. (2016). Intraneuro- Logan, T., Simon, M.J., Rana, A., Cherf, G.M., Srivastava, A., Davis, S.S., Low,
nal aggregation of the beta-CTF fragment of APP (C99) induces Abeta-inde- R.L.Y., Chiu, C.L., Fang, M., Huang, F., et al. (2021). Rescue of a lysosomal stor-
pendent lysosomal-autophagic pathology. Acta Neuropathol 132, 257–276. age disorder caused by Grn loss of function with a brain penetrant progranulin
https://doi.org/10.1007/s00401-016-1577-6. biologic. Cell 184, 4651–4668.e25. https://doi.org/10.1016/j.cell.2021.08.002.
Le Guerroué, F., Eck, F., Jung, J., Starzetz, T., Mittelbronn, M., Kaulich, M., Loi, M., Raimondi, A., Morone, D., and Molinari, M. (2019). ESCRT-III-driven
and Behrends, C. (2017). Autophagosomal content profiling reveals an piecemeal micro-ER-phagy remodels the ER during recovery from ER stress.
LC3C-dependent piecemeal mitophagy pathway. Mol. Cell 68, 786–796.e6. Nat. Commun. 10, 5058. https://doi.org/10.1038/s41467-019-12991-z.
https://doi.org/10.1016/j.molcel.2017.10.029.
Lopez, A., Fleming, A., and Rubinsztein, D.C. (2018). Seeing is believing:
Lee, H.J., Yoon, Y.S., and Lee, S.J. (2018). Mechanism of neuroprotection by
methods to monitor vertebrate autophagy in vivo. Open Biol 8, 180106.
trehalose: controversy surrounding autophagy induction. Cell Death Dis 9,
https://doi.org/10.1098/rsob.180106.
712. https://doi.org/10.1038/s41419-018-0749-9.
Lee, J.A., Beigneux, A., Ahmad, S.T., Young, S.G., and Gao, F.B. (2007). Lu, K., den Brave, F., and Jentsch, S. (2017). Receptor oligomerization guides
ESCRT-III dysfunction causes autophagosome accumulation and neurode- pathway choice between proteasomal and autophagic degradation. Nat. Cell
generation. Curr. Biol. 17, 1561–1567. https://doi.org/10.1016/j.cub.2007. Biol. 19, 732–739. https://doi.org/10.1038/ncb3531.
07.029.
Lucin, K.M., O’Brien, C.E., Bieri, G., Czirr, E., Mosher, K.I., Abbey, R.J., Mas-
Lee, J.H., Yu, W.H., Kumar, A., Lee, S., Mohan, P.S., Peterhoff, C.M., Wolfe, troeni, D.F., Rogers, J., Spencer, B., Masliah, E., and Wyss-Coray, T. (2013).
D.M., Martinez-Vicente, M., Massey, A.C., Sovak, G., et al. (2010). Lysosomal Microglial beclin 1 regulates retromer trafficking and phagocytosis and is
proteolysis and autophagy require presenilin 1 and are disrupted by Alz- impaired in Alzheimer’s disease. Neuron 79, 873–886. https://doi.org/10.
heimer-related PS1 mutations. Cell 141, 1146–1158. https://doi.org/10.1016/ 1016/j.neuron.2013.06.046.
j.cell.2010.05.008.
Luis-Ravelo, D., Estévez-Silva, H., Barroso-Chinea, P., Afonso-Oramas, D.,
Lee, M.Y., Sumpter, R., Zou, Z., Sirasanagandla, S., Wei, Y., Mishra, P., Rose- Salas-Hernández, J., Rodrı́guez-Núñez, J., Acevedo-Arozena, A., Marcellino,
wich, H., Crane, D.I., and Levine, B. (2017). Peroxisomal protein PEX13 func- D., and González-Hernández, T. (2018). Pramipexole reduces soluble mutant
tions in selective autophagy. EMBO Rep 18, 48–60. https://doi.org/10.15252/ huntingtin and protects striatal neurons through dopamine D3 receptors in a
embr.201642443. genetic model of Huntington’s disease. Exp. Neurol. 299, 137–147. https://
doi.org/10.1016/j.expneurol.2017.10.019.
Lee, Y.S., Lai, D.M., Huang, H.J., Lee-Chen, G.J., Chang, C.H., Hsieh-Li, H.M.,
and Lee, G.C. (2021). Prebiotic lactulose ameliorates the cognitive deficit in Luo, R., Su, L.Y., Li, G., Yang, J., Liu, Q., Yang, L.X., Zhang, D.F., Zhou, H., Xu,
Alzheimer’s disease mouse model through macroautophagy and chap- M., Fan, Y., et al. (2020). Activation of PPARA-mediated autophagy reduces
erone-mediated autophagy pathways. J. Agric. Food Chem. 69, 2422–2437. Alzheimer disease-like pathology and cognitive decline in a murine model.
https://doi.org/10.1021/acs.jafc.0c07327. Autophagy 16, 52–69. https://doi.org/10.1080/15548627.2019.1596488.
960 Neuron 110, March 16, 2022

ll
Review
Maeda, S., Otomo, C., and Otomo, T. (2019). The autophagic membrane tether (2014). PICALM modulates autophagy activity and tau accumulation. Nat.
ATG2A transfers lipids between membranes. eLife 8, e45777. https://doi.org/ Commun. 5, 4998. https://doi.org/10.1038/ncomms5998.
10.7554/eLife.45777.
Morozova, K., Clement, C.C., Kaushik, S., Stiller, B., Arias, E., Ahmad, A.,
Magalhaes, J., Gegg, M.E., Migdalska-Richards, A., Doherty, M.K., Whitfield, Rauch, J.N., Chatterjee, V., Melis, C., Scharf, B., et al. (2016). Structural and
P.D., and Schapira, A.H.V. (2016). Autophagic lysosome reformation dysfunc- Biological Interaction of hsc-70 Protein with phosphatidylserine in endosomal
tion in glucocerebrosidase deficient cells: relevance to Parkinson disease. microautophagy. J. Biol. Chem. 291, 18096–18106. https://doi.org/10.1074/
Hum. Mol. Genet. 25, 3432–3445. https://doi.org/10.1093/hmg/ddw185. jbc.M116.736744.
Majid, T., Ali, Y.O., Venkitaramani, D.V., Jang, M.K., Lu, H.C., and Pautler, R.G. Mukherjee, A., Patel, B., Koga, H., Cuervo, A.M., and Jenny, A. (2016). Selec-
(2014). In vivo axonal transport deficits in a mouse model of fronto-temporal tive endosomal microautophagy is starvation-inducible in Drosophila. Auto-
dementia. NeuroImage Clin 4, 711–717. https://doi.org/10.1016/j.nicl.2014. phagy 12, 1984–1999. https://doi.org/10.1080/15548627.2016.1208887.
02.005.
Murphy, K.E., Gysbers, A.M., Abbott, S.K., Tayebi, N., Kim, W.S., Sidransky,
Martinez-Vicente, M. (2017). Neuronal mitophagy in neurodegenerative dis- E., Cooper, A., Garner, B., and Halliday, G.M. (2014). Reduced glucocerebro-
eases. Front. Mol. Neurosci. 10, 64. https://doi.org/10.3389/fnmol. sidase is associated with increased a-synuclein in sporadic Parkinson’s dis-
2017.00064. ease. Brain 137, 834–848. https://doi.org/10.1093/brain/awt367.
Martinez-Vicente, M., Talloczy, Z., Kaushik, S., Massey, A.C., Mazzulli, J., Narendra, D., Kane, L.A., Hauser, D.N., Fearnley, I.M., and Youle, R.J. (2010).
Mosharov, E.V., Hodara, R., Fredenburg, R., Wu, D.C., Follenzi, A., et al. p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not
(2008). Dopamine-modified alpha-synuclein blocks chaperone-mediated mitophagy; VDAC1 is dispensable for both. Autophagy 6, 1090–1106.
autophagy. J. Clin. Invest. 118, 777–788. https://doi.org/10.1172/jci32806. https://doi.org/10.4161/auto.6.8.13426.
Martinez-Vicente, M., Talloczy, Z., Wong, E., Tang, G., Koga, H., Kaushik, S., N’Diaye, E.N., Kajihara, K.K., Hsieh, I., Morisaki, H., Debnath, J., and Brown,
de Vries, R., Arias, E., Harris, S., Sulzer, D., and Cuervo, A.M. (2010). Cargo E.J. (2009). PLIC proteins or ubiquilins regulate autophagy-dependent cell sur-
recognition failure is responsible for inefficient autophagy in Huntington’s dis- vival during nutrient starvation. EMBO Rep 10, 173–179. https://doi.org/10.
ease. Nat. Neurosci. 13, 567–576. https://doi.org/10.1038/nn.2528. 1038/embor.2008.238.
Mathis, S., Goizet, C., Soulages, A., Vallat, J.M., and Masson, G.L. (2019). Ge- Nie, T., Tao, K., Zhu, L., Huang, L., Hu, S., Yang, R., Xu, P., Mao, Z., and Yang,
netics of amyotrophic lateral sclerosis: A review. J Neurol Sci 399, 217–226. Q. (2020). Chaperone-mediated autophagy controls the turnover of E3 ubiqui-
https://doi.org/10.1016/j.jns.2019.02.030. tin ligase MARCHF5 and regulates mitochondrial dynamics. Autophagy 17,
2923–2938. https://doi.org/10.1080/15548627.2020.1848128.
Matoba, K., Kotani, T., Tsutsumi, A., Tsuji, T., Mori, T., Noshiro, D., Sugita, Y.,
Nomura, N., Iwata, S., Ohsumi, Y., et al. (2020). Atg9 is a lipid scramblase that Nikoletopoulou, V., Sidiropoulou, K., Kallergi, E., Dalezios, Y., and Tavernara-
mediates autophagosomal membrane expansion. Nat. Struct. Mol. Biol. 27, kis, N. (2017). Modulation of autophagy by BDNF underlies synaptic plasticity.
1185–1193. https://doi.org/10.1038/s41594-020-00518-w. Cell Metab 26, 230–242.e5. https://doi.org/10.1016/j.cmet.2017.06.005.
Nimmerjahn, A., Kirchhoff, F., and Helmchen, F. (2005). Resting microglial cells
Matsuda, N. (2016). Phospho-ubiquitin: upending the PINK-Parkin-ubiquitin
are highly dynamic surveillants of brain parenchyma in vivo. Science 308,
cascade. J. Biochem. 159, 379–385. https://doi.org/10.1093/jb/mvv125.
1314–1318. https://doi.org/10.1126/science.1110647.
Mejlvang, J., Olsvik, H., Svenning, S., Bruun, J.A., Abudu, Y.P., Larsen, K.B.,
Nishida, Y., Arakawa, S., Fujitani, K., Yamaguchi, H., Mizuta, T., Kanaseki, T.,
Brech, A., Hansen, T.E., Brenne, H., Hansen, T., et al. (2018). Starvation in-
Komatsu, M., Otsu, K., Tsujimoto, Y., and Shimizu, S. (2009). Discovery of
duces rapid degradation of selective autophagy receptors by endosomal mi-
Atg5/Atg7-independent alternative macroautophagy. Nature 461, 654–658.
croautophagy. J. Cell Biol. 217, 3640–3655. https://doi.org/10.1083/jcb.
https://doi.org/10.1038/nature08455.
201711002.
Nixon, R.A. (2013). The role of autophagy in neurodegenerative disease. Nat.
Menzies, F.M., Fleming, A., Caricasole, A., Bento, C.F., Andrews, S.P., Ashke- Med. 19, 983–997. https://doi.org/10.1038/nm.3232.
€llgrabe, J., Jackson, A., Jimenez Sanchez, M., Karabiyik, C., et al.
nazi, A., Fu
(2017). Autophagy and neurodegeneration: pathogenic mechanisms and ther- Nixon, R.A. (2020). The aging lysosome: an essential catalyst for late-onset
apeutic opportunities. Neuron 93, 1015–1034. https://doi.org/10.1016/j. neurodegenerative diseases. Biochim. Biophys. Acta Proteins Proteom.
neuron.2017.01.022. 1868, 140443. https://doi.org/10.1016/j.bbapap.2020.140443.
Mesquita, A., Glenn, J., and Jenny, A. (2020). Differential activation of eMI by Obri, A., Khrimian, L., Karsenty, G., and Oury, F. (2018). Osteocalcin in the
distinct forms of cellular stress. Autophagy 17, 1828–1840. https://doi.org/10. brain: from embryonic development to age-related decline in cognition. Nat.
1080/15548627.2020.1783833. Rev. Endocrinol. 14, 174–182. https://doi.org/10.1038/nrendo.2017.181.
Misgeld, T., and Schwarz, T.L. (2017). Mitostasis in neurons: maintaining mito- Ochaba, J., Lukacsovich, T., Csikos, G., Zheng, S., Margulis, J., Salazar, L.,
chondria in an extended cellular architecture. Neuron 96, 651–666. https://doi. Mao, K., Lau, A.L., Yeung, S.Y., Humbert, S., et al. (2014). Potential function
org/10.1016/j.neuron.2017.09.055. for the huntingtin protein as a scaffold for selective autophagy. Proc. Natl.
Acad. Sci. USA 111, 16889–16894. https://doi.org/10.1073/pnas.
Mizielinska, S., Lashley, T., Norona, F.E., Clayton, E.L., Ridler, C.E., Fratta, P., 1420103111.
and Isaacs, A.M. (2013). C9orf72 frontotemporal lobar degeneration is charac-
terised by frequent neuronal sense and antisense RNA foci. Acta Neuropathol Okerlund, N.D., Schneider, K., Leal-Ortiz, S., Montenegro-Venegas, C., Kim,
126, 845–857. https://doi.org/10.1007/s00401-013-1200-z. S.A., Garner, L.C., Waites, C.L., Gundelfinger, E.D., Reimer, R.J., and Garner,
C.C. (2017). Bassoon controls presynaptic autophagy through Atg5. Neuron
Mizushima, N., Yoshimori, T., and Ohsumi, Y. (2011). The role of Atg proteins in 93, 897–913. e897. https://doi.org/10.1016/j.neuron.2017.01.026.
autophagosome formation. Annu. Rev. Cell Dev. Biol. 27, 107–132. https://doi.
org/10.1146/annurev-cellbio-092910-154005. Orenstein, S.J., Kuo, S.H., Tasset, I., Arias, E., Koga, H., Fernandez-Carasa, I.,
Cortes, E., Honig, L.S., Dauer, W., Consiglio, A., et al. (2013). Interplay of
Moore, A.S., and Holzbaur, E.L. (2016). Dynamic recruitment and activation of LRRK2 with chaperone-mediated autophagy. Nat. Neurosci. 16, 394–406.
ALS-associated TBK1 with its target optineurin are required for efficient mi- https://doi.org/10.1038/nn.3350.
tophagy. Proc. Natl. Acad. Sci. USA 113, E3349–E3358. https://doi.org/10.
1073/pnas.1523810113. Osawa, T., Mizuno, Y., Fujita, Y., Takatama, M., Nakazato, Y., and Okamoto,
K. (2011). Optineurin in neurodegenerative diseases. Neuropathology 31,
Morales, I., Sanchez, A., Puertas-Avendaño, R., Rodriguez-Sabate, C., Perez- 569–574. https://doi.org/10.1111/j.1440-1789.2011.01199.x.
Barreto, A., and Rodriguez, M. (2020). Neuroglial transmitophagy and Parkin-
son’s disease. Glia 68, 2277–2299. https://doi.org/10.1002/glia.23839. Oz-Levi, D., Ben-Zeev, B., Ruzzo, E.K., Hitomi, Y., Gelman, A., Pelak, K., Anik-
ster, Y., Reznik-Wolf, H., Bar-Joseph, I., Olender, T., et al. (2012). Mutation in
Moreau, K., Fleming, A., Imarisio, S., Lopez Ramirez, A., Mercer, J.L., Jime- TECPR2 reveals a role for autophagy in hereditary spastic paraparesis. Am. J.
nez-Sanchez, M., Bento, C.F., Puri, C., Zavodszky, E., Siddiqi, F., et al. Hum. Genet. 91, 1065–1072. https://doi.org/10.1016/j.ajhg.2012.09.015.
Neuron 110, March 16, 2022 961

ll
Review
Paiva, S.L., and Crews, C.M. (2019). Targeted protein degradation: elements Puri, C., Manni, M.M., Vicinanza, M., Hilcenko, C., Zhu, Y., Runwal, G., Stama-
of Protac design. Curr. Opin. Chem. Biol. 50, 111–119. https://doi.org/10. takou, E., Menzies, F.M., Mamchaoui, K., Bitoun, M., and Rubinsztein, D.C.
1016/j.cbpa.2019.02.022. (2020). A DNM2 centronuclear myopathy mutation reveals a link between recy-
cling endosome scission and autophagy. Dev. Cell 53, 154–168.e6. https://doi.
€e, Á.J., Escoll, M., de Ceballos,
Pajares, M., Jiménez-Moreno, N., Garcı́a-Yagu org/10.1016/j.devcel.2020.03.018.
M.L., Van Leuven, F., Rábano, A., Yamamoto, M., Rojo, A.I., and Cuadrado, A.
(2016). Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy Puri, C., Renna, M., Bento, C.F., Moreau, K., and Rubinsztein, D.C. (2013).
genes. Autophagy 12, 1902–1916. https://doi.org/10.1080/15548627.2016. Diverse autophagosome membrane sources coalesce in recycling endo-
1208889. somes. Cell 154, 1285–1299. https://doi.org/10.1016/j.cell.2013.08.044.
Pang, S., Chen, D., Zhang, A., Qin, X., and Yan, B. (2012). Genetic analysis of Puri, C., Vicinanza, M., Ashkenazi, A., Gratian, M.J., Zhang, Q., Bento, C.F.,
the LAMP-2 gene promoter in patients with sporadic Parkinson’s disease. Renna, M., Menzies, F.M., and Rubinsztein, D.C. (2018). The RAB11A-positive
Neurosci. Lett. 526, 63–67. https://doi.org/10.1016/j.neulet.2012.07.044. compartment is a primary platform for autophagosome assembly mediated by
WIPI2 recognition of PI3P-RAB11A. Dev. Cell 45, 114–131.e8. https://doi.org/
Pang, W., and Hu, F. (2021). Cellular and physiological functions of C9ORF72 10.1016/j.devcel.2018.03.008.
and implications for ALS/FTD. J. Neurochem. 157, 334–350. https://doi.org/
10.1111/jnc.15255. Pyo, J.O., Yoo, S.M., Ahn, H.H., Nah, J., Hong, S.H., Kam, T.I., Jung, S., and
Jung, Y.K. (2013). Overexpression of Atg5 in mice activates autophagy and ex-
Paolicelli, R.C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P., tends lifespan. Nat. Commun. 4, 2300. https://doi.org/10.1038/ncomms3300.
Giustetto, M., Ferreira, T.A., Guiducci, E., Dumas, L., et al. (2011). Synaptic
Raj, T., Li, Y.I., Wong, G., Humphrey, J., Wang, M., Ramdhani, S., Wang, Y.C.,
pruning by microglia is necessary for normal brain development. Science
Ng, B., Gupta, I., Haroutunian, V., et al. (2018). Integrative transcriptome ana-
333, 1456–1458. https://doi.org/10.1126/science.1202529.
lyses of the aging brain implicate altered splicing in Alzheimer’s disease sus-
ceptibility. Nat. Genet. 50, 1584–1592. https://doi.org/10.1038/s41588-018-
Papadopoulos, C., Kravic, B., and Meyer, H. (2020). Repair or lysophagy: 0238-1.
dealing with damaged lysosomes. J. Mol. Biol. 432, 231–239. https://doi.
org/10.1016/j.jmb.2019.08.010. Ravikumar, B., Acevedo-Arozena, A., Imarisio, S., Berger, Z., Vacher, C.,
O’Kane, C.J., Brown, S.D., and Rubinsztein, D.C. (2005). Dynein mutations
Parcon, P.A., Balasubramaniam, M., Ayyadevara, S., Jones, R.A., Liu, L., impair autophagic clearance of aggregate-prone proteins. Nat. Genet. 37,
Shmookler Reis, R.J.S., Barger, S.W., Mrak, R.E., and Griffin, W.S.T. (2018). 771–776. https://doi.org/10.1038/ng1591.
Apolipoprotein E4 inhibits autophagy gene products through direct, specific
binding to CLEAR motifs. Alzheimers Dement 14, 230–242. https://doi.org/ Ravikumar, B., Imarisio, S., Sarkar, S., O’Kane, C.J., and Rubinsztein, D.C.
10.1016/j.jalz.2017.07.754. (2008). Rab5 modulates aggregation and toxicity of mutant huntingtin through
macroautophagy in cell and fly models of Huntington disease. J. Cell Sci. 121,
Park, J.S., Kim, D.H., and Yoon, S.Y. (2016a). Regulation of amyloid precursor 1649–1660. https://doi.org/10.1242/jcs.025726.
protein processing by its KFERQ motif. BMB Rep 49, 337–342. https://doi.org/
10.5483/bmbrep.2016.49.6.212. Raybould, R., and Sims, R. (2021). Searching the Dark Genome for Alzheimer’s
Disease Risk Variants. Brain Sci 11, 332. https://doi.org/10.3390/
Park, S., Han, S., Choi, I., Kim, B., Park, S.P., Joe, E.H., and Suh, Y.H. (2016b). brainsci11030332.
Interplay between leucine-rich repeat kinase 2 (LRRK2) and p62/SQSTM-1 in
selective autophagy. PLoS One 11, e0163029. https://doi.org/10.1371/jour- Reddy, A.B., and Rey, G. (2014). Metabolic and nontranscriptional circadian
nal.pone.0163029. clocks: eukaryotes. Annu. Rev. Biochem. 83, 165–189. https://doi.org/10.
1146/annurev-biochem-060713-035623.
Park, S.J., Frake, R.A., Karabiyik, C., Son, S.M., Siddiqi, F.H., Bento, C.F.,
Sterk, P., Vicinanza, M., Pavel, M., and Rubinsztein, D.C. (2021). Vinexin con- Renton, A.E., Majounie, E., Waite, A., Simón-Sánchez, J., Rollinson, S., Gibbs,
tributes to autophagic decline in brain ageing across species. Cell Death Differ. J.R., Schymick, J.C., Laaksovirta, H., van Swieten, J.C., Myllykangas, L., et al.
https://doi.org/10.1038/s41418-021-00903-y. (2011). A hexanucleotide repeat expansion in C9ORF72 is the cause of chro-
mosome 9p21-linked ALS-FTD. Neuron 72, 257–268. https://doi.org/10.
Pastore, N., Vainshtein, A., Herz, N.J., Huynh, T., Brunetti, L., Klisch, T.J., Mu- 1016/j.neuron.2011.09.010.
tarelli, M., Annunziata, P., Kinouchi, K., Brunetti-Pierri, N., et al. (2019).
Nutrient-sensitive transcription factors TFEB and TFE3 couple autophagy Ribeiro, F.M., Devries, R.A., Hamilton, A., Guimaraes, I.M., Cregan, S.P., Pires,
and metabolism to the peripheral clock. EMBO J 38. https://doi.org/10. R.G., and Ferguson, S.S. (2014). Metabotropic glutamate receptor 5 knockout
15252/embj.2018101347. promotes motor and biochemical alterations in a mouse model of Huntington’s
disease. Hum. Mol. Genet. 23, 2030–2042. https://doi.org/10.1093/hmg/
Pérez, M., Avila, J., and Hernández, F. (2019). Propagation of tau via extracel- ddt598.
lular vesicles. Front. Neurosci. 13, 698. https://doi.org/10.3389/fnins.
Richter, B., Sliter, D.A., Herhaus, L., Stolz, A., Wang, C., Beli, P., Zaffagnini, G.,
2019.00698.
Wild, P., Martens, S., Wagner, S.A., et al. (2016). Phosphorylation of OPTN by
TBK1 enhances its binding to Ub chains and promotes selective autophagy of
Pickford, F., Masliah, E., Britschgi, M., Lucin, K., Narasimhan, R., Jaeger, P.A.,
damaged mitochondria. Proc. Natl. Acad. Sci. USA 113, 4039–4044. https://
Small, S., Spencer, B., Rockenstein, E., Levine, B., and Wyss-Coray, T. (2008).
doi.org/10.1073/pnas.1523926113.
The autophagy-related protein beclin 1 shows reduced expression in early Alz-
heimer disease and regulates amyloid beta accumulation in mice. J. Clin. Rodrı́guez-Muela, N., Koga, H., Garcı́a-Ledo, L., de la Villa, P., de la Rosa, E.J.,
Invest. 118, 2190–2199. https://doi.org/10.1172/Jci33585. Cuervo, A.M., and Boya, P. (2013). Balance between autophagic pathways
preserves retinal homeostasis. Aging Cell 12, 478–488. https://doi.org/10.
Pilli, M., Arko-Mensah, J., Ponpuak, M., Roberts, E., Master, S., Mandell, M.A., 1111/acel.12072.
Dupont, N., Ornatowski, W., Jiang, S., Bradfute, S.B., et al. (2012). TBK-1 pro-
motes autophagy-mediated antimicrobial defense by controlling autophago- Rothenberg, C., Srinivasan, D., Mah, L., Kaushik, S., Peterhoff, C.M., Ugolino,
some maturation. Immunity 37, 223–234. https://doi.org/10.1016/j.immuni. J., Fang, S., Cuervo, A.M., Nixon, R.A., and Monteiro, M.J. (2010). Ubiquilin
2012.04.015. functions in autophagy and is degraded by chaperone-mediated autophagy.
Hum. Mol. Genet. 19, 3219–3232. https://doi.org/10.1093/hmg/ddq231.
Pirooznia, S.K., Yuan, C., Khan, M.R., Karuppagounder, S.S., Wang, L., Xiong,
Y., Kang, S.U., Lee, Y., Dawson, V.L., and Dawson, T.M. (2020). Paris induced Rubinsztein, D.C., and Orr, H.T. (2016). Diminishing return for mechanistic
defects in mitochondrial biogenesis drive dopamine neuron loss under condi- therapeutics with neurodegenerative disease duration?: there may be a point
tions of parkin or PINK1 deficiency. Mol. Neurodegener. 15, 17. https://doi. in the course of a neurodegenerative condition where therapeutics targeting
org/10.1186/s13024-020-00363-x. disease-causing mechanisms are futile. BioEssays 38, 977–980. https://doi.
org/10.1002/bies.201600048.
Puls, I., Jonnakuty, C., LaMonte, B.H., Holzbaur, E.L., Tokito, M., Mann, E.,
Floeter, M.K., Bidus, K., Drayna, D., Oh, S.J., et al. (2003). Mutant dynactin Rudnick, N.D., Griffey, C.J., Guarnieri, P., Gerbino, V., Wang, X., Piersaint,
in motor neuron disease. Nat. Genet. 33, 455–456. https://doi.org/10.1038/ J.A., Tapia, J.C., Rich, M.M., and Maniatis, T. (2017). Distinct roles for motor
ng1123. neuron autophagy early and late in the SOD1(G93A) mouse model of ALS.
962 Neuron 110, March 16, 2022

ll
Review
Proc. Natl. Acad. Sci. USA 114, E8294–E8303. https://doi.org/10.1073/pnas. Settembre, C., Fraldi, A., Medina, D.L., and Ballabio, A. (2013). Signals from
1704294114. the lysosome: a control centre for cellular clearance and energy metabolism.
Nat. Rev. Mol. Cell Biol. 14, 283–296. https://doi.org/10.1038/nrm3565.
Rui, Y.N., Xu, Z., Patel, B., Chen, Z., Chen, D., Tito, A., David, G., Sun, Y.,
Stimming, E.F., Bellen, H.J., et al. (2015). Huntingtin functions as a scaffold Sha, Z., Schnell, H.M., Ruoff, K., and Goldberg, A. (2018). Rapid induction of
for selective macroautophagy. Nat. Cell Biol. 17, 262–275. https://doi.org/ p62 and GABARAPL1 upon proteasome inhibition promotes survival before
10.1038/ncb3101. autophagy activation. J. Cell Biol. 217, 1757–1776. https://doi.org/10.1083/
jcb.201708168.
Ryskalin, L., Limanaqi, F., Frati, A., Busceti, C.L., and Fornai, F. (2018). mTOR-
related brain dysfunctions in neuropsychiatric disorders. Int. J. Mol. Sci. 19, Shehata, M., Matsumura, H., Okubo-Suzuki, R., Ohkawa, N., and Inokuchi, K.
2226. https://doi.org/10.3390/ijms19082226. (2012). Neuronal stimulation induces autophagy in hippocampal neurons that
is involved in AMPA receptor degradation after chemical long-term depres-
Sahu, R., Kaushik, S., Clement, C.C., Cannizzo, E.S., Scharf, B., Follenzi, A., sion. J. Neurosci. 32, 10413–10422. https://doi.org/10.1523/JNEUROSCI.
Potolicchio, I., Nieves, E., Cuervo, A.M., and Santambrogio, L. (2011). Micro- 4533-11.2012.
autophagy of cytosolic proteins by late endosomes. Dev. Cell 20, 131–139.
https://doi.org/10.1016/j.devcel.2010.12.003. Shen, W.C., Li, H.Y., Chen, G.C., Chern, Y., and Tu, P.H. (2015). Mutations in
the ubiquitin-binding domain of OPTN/optineurin interfere with autophagy-
Saitsu, H., Nishimura, T., Muramatsu, K., Kodera, H., Kumada, S., Sugai, K., mediated degradation of misfolded proteins by a dominant-negative mecha-
Kasai-Yoshida, E., Sawaura, N., Nishida, H., Hoshino, A., et al. (2013). De nism. Autophagy 11, 685–700. https://doi.org/10.4161/auto.36098.
novo mutations in the autophagy gene WDR45 cause static encephalopathy
of childhood with neurodegeneration in adulthood. Nat. Genet. 45, 445–449. Shen, Z., Li, Y., Gasparski, A.N., Abeliovich, H., and Greenberg, M.L. (2017).
e441. https://doi.org/10.1038/ng.2562. Cardiolipin regulates mitophagy through the protein kinase C pathway.
J. Biol. Chem. 292, 2916–2923. https://doi.org/10.1074/jbc.M116.753574.
Sala, G., Marinig, D., Arosio, A., and Ferrarese, C. (2016). Role of chaperone-
mediated autophagy dysfunctions in the pathogenesis of Parkinson’s disease. Shin, J.H., Ko, H.S., Kang, H., Lee, Y., Lee, Y.I., Pletinkova, O., Troconso, J.C.,
Front. Mol. Neurosci. 9, 157. https://doi.org/10.3389/fnmol.2016.00157. Dawson, V.L., and Dawson, T.M. (2011). PARIS (ZNF746) repression of PGC-
1alpha contributes to neurodegeneration in Parkinson’s disease. Cell 144,
Sancak, Y., Peterson, T.R., Shaul, Y.D., Lindquist, R.A., Thoreen, C.C., Bar- 689–702. https://doi.org/10.1016/j.cell.2011.02.010.
Peled, L., and Sabatini, D.M. (2008). The Rag GTPases bind raptor and
mediate amino acid signaling to mTORC1. Science 320, 1496–1501. https:// Siddiqi, F.H., Menzies, F.M., Lopez, A., Stamatakou, E., Karabiyik, C., Ure-
doi.org/10.1126/science.1157535. shino, R., Ricketts, T., Jimenez-Sanchez, M., Esteban, M.A., Lai, L.X., et al.
(2019). Felodipine induces autophagy in mouse brains with pharmacokinetics
Sanchez-Martin, P., Lahuerta, M., Viana, R., Knecht, E., and Sanz, P. (2020). amenable to repurposing. Nat. Commun. 10, 1817. https://doi.org/10.1038/
Regulation of the autophagic PI3KC3 complex by laforin/malin E3-ubiquitin s41467-019-09494-2.
ligase, two proteins involved in Lafora disease. Biochim. Biophys. Acta Mol.
Cell Res. 1867, 118613. https://doi.org/10.1016/j.bbamcr.2019.118613. Simonovitch, S., Schmukler, E., Bespalko, A., Iram, T., Frenkel, D., Holtzman,
D.M., Masliah, E., Michaelson, D.M., and Pinkas-Kramarski, R. (2016).
Sarkar, S., Olsen, A.L., Sygnecka, K., Lohr, K.M., and Feany, M.B. (2021). A-
Impaired autophagy in APOE4 astrocytes. J. Alzheimers Dis. 51, 915–927.
synuclein impairs autophagosome maturation through abnormal actin stabili-
https://doi.org/10.3233/Jad-151101.
zation. PLoS Genet 17, e1009359. https://doi.org/10.1371/JOURNAL.PGEN.
1009359.
Simonsen, A., Cumming, R.C., Brech, A., Isakson, P., Schubert, D.R., and Fin-
ley, K.D. (2008). Promoting basal levels of autophagy in the nervous system en-
Sarraf, S.A., Shah, H.V., Kanfer, G., Pickrell, A.M., Holtzclaw, L.A., Ward, M.E.,
hances longevity and oxidant resistance in adult Drosophila. Autophagy 4,
and Youle, R.J. (2020). Loss of TAX1BP1-directed autophagy results in protein
176–184. https://doi.org/10.4161/auto.5269.
aggregate accumulation in the brain. Mol. Cell 80, 779–795.e10. https://doi.
org/10.1016/j.molcel.2020.10.041.
Son, S.M., Park, S.J., Stamatakou, E., Vicinanza, M., Menzies, F.M., and Ru-
Saxton, R.A., and Sabatini, D.M. (2017). mTOR signaling in growth, meta- binsztein, D.C. (2020). Leucine regulates autophagy via acetylation of the
bolism, and disease. Cell 169, 361–371. https://doi.org/10.1016/j.cell.2017. mTORC1 component raptor. Nat. Commun. 11, 3148. https://doi.org/10.
03.035. 1038/s41467-020-16886-2.
Schneider, J.L., Villarroya, J., Diaz-Carretero, A., Patel, B., Urbanska, A.M., Song, G.J., Jeon, H., Seo, M., Jo, M., and Suk, K. (2018). Interaction between
Thi, M.M., Villarroya, F., Santambrogio, L., and Cuervo, A.M. (2015). Loss of optineurin and Rab1a regulates autophagosome formation in neuroblastoma
hepatic chaperone-mediated autophagy accelerates proteostasis failure in cells. J. Neurosci. Res. 96, 407–415. https://doi.org/10.1002/jnr.24143.
aging. Aging Cell 14, 249–264. https://doi.org/10.1111/acel.12310.
Spillantini, M.G., Schmidt, M.L., Lee, V.M.-Y., Trojanowski, J.Q., Jakes, R.,
Schöndorf, D.C., Aureli, M., Mcallister, F.E., Hindley, C.J., Mayer, F., Scho, and Goedert, M. (1997). a-Synuclein in Lewy bodies. Nature 388, 839–840.
D.C., Schmid, B., Sardi, S.P., Valsecchi, M., Hoffmann, S., et al. (2014).
iPSC-derived neurons from GBA1-associated Parkinson’s disease patients Stadel, D., Millarte, V., Tillmann, K.D., Huber, J., Tamin-Yecheskel, B.C.,
show autophagic defects and impaired calcium homeostasis. Nat. Commun. Akutsu, M., Demishtein, A., Ben-Zeev, B., Anikster, Y., Perez, F., et al.
5, 1–17. https://doi.org/10.1038/ncomms5028. (2015). TECPR2 cooperates with LC3C to regulate COPII-dependent ER
export. Mol. Cell 60, 89–104. https://doi.org/10.1016/j.molcel.2015.09.010.
Schreiber, S.L. (2021). The rise of molecular glues. Cell 184, 3–9. https://doi.
org/10.1016/j.cell.2020.12.020. Stamatakou, E., Wróbel, L., Hill, S.M., Puri, C., Son, S.M., Fujimaki, M., Zhu, Y.,
Siddiqi, F., Fernandez-Estevez, M., Manni, M.M., et al. (2020). Mendelian
Schuck, S. (2020). Microautophagy - distinct molecular mechanisms handle neurodegenerative disease genes involved in autophagy. Cell Discov 6, 24.
cargoes of many sizes. J. Cell Sci. 133. https://doi.org/10.1242/jcs.246322. https://doi.org/10.1038/s41421-020-0158-y.
Scrivo, A., Bourdenx, M., Pampliega, O., and Cuervo, A.M. (2018). Selective Stavoe, A.K.H., and Holzbaur, E.L.F. (2019). Autophagy in neurons. Annu. Rev.
autophagy as a potential therapeutic target for neurodegenerative disorders. Cell Dev. Biol. 35, 477–500. https://doi.org/10.1146/annurev-cellbio-100818-
Lancet Neurol 17, 802–815. https://doi.org/10.1016/S1474-4422(18)30238-2. 125242.
Seibenhener, M.L., Babu, J.R., Geetha, T., Wong, H.C., Krishna, N.R., and Steckley, D., Karajgikar, M., Dale, L.B., Fuerth, B., Swan, P., Drummond-Main,
Wooten, M.W. (2004). Sequestosome 1/p62 is a polyubiquitin chain binding C., Poulter, M.O., Ferguson, S.S., Strasser, A., and Cregan, S.P. (2007). Puma
protein involved in ubiquitin proteasome degradation. Mol. Cell. Biol. 24, is a dominant regulator of oxidative stress induced Bax activation and neuronal
8055–8068. https://doi.org/10.1128/MCB.24.18.8055-8068.2004. apoptosis. J. Neurosci. 27, 12989–12999. https://doi.org/10.1523/JNEURO-
SCI.3400-07.2007.
€rk, M., Lin, G., Zuo, Z., Mao, D., Watson, E., Mikos, A.G., and Bellen, H.J.
Sxentu
(2019). Ubiquilins regulate autophagic flux through mTOR signalling and lyso- Stefanis, L., Larsen, K.E., Rideout, H.J., Sulzer, D., and Greene, L.A. (2001).
somal acidification. Nat. Cell Biol. 21, 384–396. https://doi.org/10.1038/ Expression of A53T mutant but not wild-type a-synuclein in PC12 cells induces
s41556-019-0281-x. alterations of the ubiquitin-dependent degradation system, loss of dopamine
Neuron 110, March 16, 2022 963

ll
Review
release, and autophagic cell death. J. Neurosci. 21, 9549–9560. https://doi. Tresse, E., Salomons, F.A., Vesa, J., Bott, L.C., Kimonis, V., Yao, T.P., Dan-
org/10.1523/jneurosci.21-24-09549.2001. tuma, N.P., and Taylor, J.P. (2010). VCP/p97 is essential for maturation of ubiq-
uitin-containing autophagosomes and this function is impaired by mutations
Stevens, D.A., Lee, Y., Kang, H.C., Lee, B.D., Lee, Y.I., Bower, A., Jiang, H., that cause IBMPFD. Autophagy 6, 217–227. https://doi.org/10.4161/auto.6.
Kang, S.U., Andrabi, S.A., Dawson, V.L., et al. (2015). Parkin loss leads to 2.11014.
PARIS-dependent declines in mitochondrial mass and respiration. Proc.
Natl. Acad. Sci. USA 112, 11696–11701. https://doi.org/10.1073/pnas. Tumbarello, D.A., Waxse, B.J., Arden, S.D., Bright, N.A., Kendrick-Jones, J.,
1500624112. and Buss, F. (2012). Autophagy receptors link myosin VI to autophagosomes
to mediate Tom1-dependent autophagosome maturation and fusion with the
Stykel, M.G., Humphries, K.M., Kamski-Hennekam, E., Buchner-Duby, B., lysosome. Nat. Cell Biol. 14, 1024–1035. https://doi.org/10.1038/ncb2589.
Porte-Trachsel, N., Ryan, T., Coackley, C.L., Bamm, V.V., Harauz, G., and
Ryan, S.D. (2021). a-Synuclein mutation impairs processing of endomem- Ugolino, J., Ji, Y.J., Conchina, K., Chu, J., Nirujogi, R.S., Pandey, A., Brady,
brane compartments and promotes exocytosis and seeding of a-synuclein pa- N.R., Hamacher-Brady, A., and Wang, J. (2016). Loss of C9orf72 enhances au-
thology. Cell Rep 35, 109099. https://doi.org/10.1016/j.celrep.2021.109099. tophagic activity via deregulated mTOR and TFEB signaling. PLOS Genet 12,
e1006443. https://doi.org/10.1371/journal.pgen.1006443.
Sun, N., Yun, J., Liu, J., Malide, D., Liu, C., Rovira, I.I., Holmström, K.M., Fer-
gusson, M.M., Yoo, Y.H., Combs, C.A., and Finkel, T. (2015). Measuring in vivo Uytterhoeven, V., Lauwers, E., Maes, I., Miskiewicz, K., Melo, M.N., Swerts, J.,
mitophagy. Mol. Cell 60, 685–696. https://doi.org/10.1016/j.molcel.2015. Kuenen, S., Wittocx, R., Corthout, N., Marrink, S.J., et al. (2015). Hsc70-4 de-
10.009. forms membranes to promote synaptic protein turnover by endosomal micro-
autophagy. Neuron 88, 735–748. https://doi.org/10.1016/j.neuron.2015.
Sundaramoorthy, V., Walker, A.K., Tan, V., Fifita, J.A., Mccann, E.P., Williams, 10.012.
K.L., Blair, I.P., Guillemin, G.J., Farg, M.A., and Atkin, J.D. (2015). Defects in
optineurin- and myosin VI-mediated cellular trafficking in amyotrophic lateral Valek, L., Heidler, J., Scheving, R., Wittig, I., and Tegeder, I. (2019). Nitric oxide
sclerosis. Hum. Mol. Genet. 24, 3830–3846. https://doi.org/10.1093/hmg/ contributes to protein homeostasis by S-nitrosylations of the chaperone
ddv126. HSPA8 and the ubiquitin ligase UBE2D. Redox Biol 20, 217–235. https://doi.
org/10.1016/j.redox.2018.10.002.
Sun-Wang, J.L., Ivanova, S., and Zorzano, A. (2020). The dialogue between the
ubiquitin-proteasome system and autophagy: implications in ageing. Ageing van Waarde, A., Marcolini, S., de Deyn, P.P., and Dierckx, R.A.J.O. (2021). PET
Res. Rev. 64, 101203. https://doi.org/10.1016/j.arr.2020.101203. agents in dementia: an overview. Semin. Nucl. Med. 51, 196–229. https://doi.
org/10.1053/j.semnuclmed.2020.12.008.
Takahashi, D., Moriyama, J., Nakamura, T., Miki, E., Takahashi, E., Sato, A.,
Akaike, T., Itto-Nakama, K., and Arimoto, H. (2019). AUTACs: cargo-specific Vantaggiato, C., Crimella, C., Airoldi, G., Polishchuk, R., Bonato, S., Brighina,
degraders using selective autophagy. Mol. Cell 76, 797–810.e10. https://doi. E., Scarlato, M., Musumeci, O., Toscano, A., Martinuzzi, A., et al. (2013).
org/10.1016/j.molcel.2019.09.009. Defective autophagy in spastizin mutated patients with hereditary spastic par-
aparesis type 15. Brain 136, 3119–3139. https://doi.org/10.1093/brain/
Takahashi, Y., He, H., Tang, Z., Hattori, T., Liu, Y., Young, M.M., Serfass, J.M., awt227.
Chen, L., Gebru, M., Chen, C., et al. (2018). An autophagy assay reveals the
ESCRT-III component CHMP2A as a regulator of phagophore closure. Nat. Vantaggiato, C., Panzeri, E., Castelli, M., Citterio, A., Arnoldi, A., Santorelli,
Commun. 9, 2855. https://doi.org/10.1038/s41467-018-05254-w. F.M., Liguori, R., Scarlato, M., Musumeci, O., Toscano, A., et al. (2019).
ZFYVE26/SPASTIZIN and SPG11/SPATACSIN mutations in hereditary spastic
Tamaki, Y., Shodai, A., Morimura, T., Hikiami, R., Minamiyama, S., Ayaki, T., paraplegia types AR-SPG15 and AR-SPG11 have different effects on auto-
Tooyama, I., Furukawa, Y., Takahashi, R., and Urushitani, M. (2018). Elimina- phagy and endocytosis. Autophagy 15, 34–57. https://doi.org/10.1080/
tion of TDP-43 inclusions linked to amyotrophic lateral sclerosis by a misfold- 15548627.2018.1507438.
ing-specific intrabody with dual proteolytic signals. Sci. Rep. 8, 6030. https://
doi.org/10.1038/s41598-018-24463-3. Vaz-Silva, J., Gomes, P., Jin, Q., Zhu, M., Zhuravleva, V., Quintremil, S., Meira,
T., Silva, J., Dioli, C., Soares-Cunha, C., et al. (2018). Endolysosomal degrada-
Tang, F.-L., Erion, J.R., Tian, Y., Liu, W., Yin, D.-M., Ye, J., Tang, B., Mei, L., tion of Tau and its role in glucocorticoid-driven hippocampal malfunction.
and Xiong, W.-C. (2015). VPS35 in dopamine neurons is required for endo- EMBO J 37, e99084. https://doi.org/10.15252/embj.201899084.
some-to-Golgi retrieval of Lamp2a, a receptor of chaperone-mediated auto-
phagy that is critical for a-synuclein degradation and prevention of pathogen- Verhoeven, K., De Jonghe, P., Coen, K., Verpoorten, N., Auer-Grumbach, M.,
esis of Parkinson’s disease. J. Neurosci. 35, 10613–10628. https://doi.org/10. Kwon, J.M., FitzPatrick, D., Schmedding, E., De Vriendt, E., Jacobs, A., et al.
1523/JNEUROSCI.0042-15.2015. (2003). Mutations in the small GTP-ase late endosomal protein RAB7 cause
Charcot-Marie-Tooth type 2B neuropathy. Am. J. Hum. Genet. 72, 722–727.
Tang, G., Gudsnuk, K., Kuo, S.H., Cotrina, M.L., Rosoklija, G., Sosunov, A., https://doi.org/10.1086/367847.
Sonders, M.S., Kanter, E., Castagna, C., Yamamoto, A., et al. (2014). Loss
of mTOR-dependent macroautophagy causes autistic-like synaptic pruning Vicinanza, M., Korolchuk, V.I., Ashkenazi, A., Puri, C., Menzies, F.M., Clarke,
deficits. Neuron 83, 1131–1143. https://doi.org/10.1016/j.neuron.2014. J.H., and Rubinsztein, D.C. (2015). PI(5)P regulates autophagosome biogen-
07.040. esis. Mol. Cell 57, 219–234. https://doi.org/10.1016/j.molcel.2014.12.007.
Tang, G., Yue, Z., Talloczy, Z., Hagemann, T., Cho, W., Messing, A., Sulzer, Volpicelli-Daley, L.A., Gamble, K.L., Schultheiss, C.E., Riddle, D.M., West,
D.L., and Goldman, J.E. (2008). Autophagy induced by Alexander disease- A.B., and Lee, V.M. (2014). Formation of a-synuclein Lewy neurite-like aggre-
mutant GFAP accumulation is regulated by p38/MAPK and mTOR signaling gates in axons impedes the transport of distinct endosomes. Mol. Biol. Cell 25,
pathways. Hum. Mol. Genet. 17, 1540–1555. https://doi.org/10.1093/hmg/ 4010–4023. https://doi.org/10.1091/mbc.E14-02-0741.
ddn042.
Wallings, R., Connor-Robson, N., and Wade-Martins, R. (2019). LRRK2 inter-
Tanik, S.A., Schultheiss, C.E., Volpicelli-Daley, L.A., Brunden, K.R., and Lee, acts with the vacuolar-type H+-ATPase pump a1 subunit to regulate lysosomal
V.M. (2013). Lewy body-like a-synuclein aggregates resist degradation and function. Hum. Mol. Genet. 28, 2696–2710. https://doi.org/10.1093/hmg/
impair macroautophagy. J. Biol. Chem. 288, 15194–15210. https://doi.org/ ddz088.
10.1074/jbc.M113.457408.
Wang, B., Cai, Z., Tao, K., Zeng, W., Lu, F., Yang, R., Feng, D., Gao, G., and
Thorburn, J., Andrysik, Z., Staskiewicz, L., Gump, J., Maycotte, P., Oberst, A., Yang, Q. (2016). Essential control of mitochondrial morphology and function
Green, D.R., Espinosa, J.M., and Thorburn, A. (2014). Autophagy controls the by chaperone-mediated autophagy through degradation of PARK7. Auto-
kinetics and extent of mitochondrial apoptosis by regulating PUMA levels. Cell phagy 12, 1215–1228. https://doi.org/10.1080/15548627.2016.1179401.
Rep 7, 45–52. https://doi.org/10.1016/j.celrep.2014.02.036.
Wang, J.D., Cao, Y.L., Li, Q., Yang, Y.P., Jin, M., Chen, D., Wang, F., Wang,
Tian, Y., Chang, J.C., Fan, E.Y., Flajolet, M., and Greengard, P. (2013). Adaptor G.H., Qin, Z.H., Hu, L.F., and Liu, C.F. (2015). A pivotal role of FOS-mediated
complex AP2/PICALM, through interaction with LC3, targets Alzheimer’s APP- BECN1/Beclin 1 upregulation in dopamine D2 and D3 receptor agonist-
CTF for terminal degradation via autophagy. Proc. Natl. Acad. Sci. USA 110, induced autophagy activation. Autophagy 11, 2057–2073. https://doi.org/10.
17071–17076. https://doi.org/10.1073/pnas.1315110110. 1080/15548627.2015.1100930.
964 Neuron 110, March 16, 2022

ll
Review
Wang, R., Tan, J., Chen, T., Han, H., Tian, R., Tan, Y., Wu, Y., Cui, J., Chen, F., Xilouri, M., Brekk, O.R., Landeck, N., Pitychoutis, P.M., Papasilekas, T., Papa-
Li, J., et al. (2019a). ATP13A2 facilitates HDAC6 recruitment to lysosome to dopoulou-Daifoti, Z., Kirik, D., and Stefanis, L. (2013). Boosting chaperone-
promote autophagosome–lysosome fusion. J. Cell Biol. 218, 267–284. mediated autophagy in vivo mitigates alpha-synuclein-induced neurodegen-
https://doi.org/10.1083/jcb.201804165. eration. Brain 136, 2130–2146. https://doi.org/10.1093/brain/awt131.
Wang, X.J., Yu, J., Wong, S.H., Cheng, A.S., Chan, F.K., Ng, S.S., Cho, C.H., Xilouri, M., Brekk, O.R., Polissidis, A., Chrysanthou-Piterou, M., Kloukina, I.,
Sung, J.J., and Wu, W.K. (2013). A novel crosstalk between two major protein and Stefanis, L. (2016). Impairment of chaperone-mediated autophagy in-
degradation systems: regulation of proteasomal activity by autophagy. Auto- duces dopaminergic neurodegeneration in rats. Autophagy 12, 2230–2247.
phagy 9, 1500–1508. https://doi.org/10.4161/auto.25573. https://doi.org/10.1080/15548627.2016.1214777.
Wang, Z.T., Lu, M.H., Zhang, Y., Ji, W.L., Lei, L., Wang, W., Fang, L.P., Wang, Xu, C.Y., Kang, W.Y., Chen, Y.M., Jiang, T.F., Zhang, J., Zhang, L.N., Ding,
L.W., Yu, F., Wang, J., et al. (2019b). Disrupted-in-schizophrenia-1 protects J.Q., Liu, J., and Chen, S.D. (2017). DJ-1 inhibits a-synuclein aggregation by
synaptic plasticity in a transgenic mouse model of Alzheimer’s disease as a mi- regulating chaperone-mediated autophagy. Front. Aging Neurosci. 9, 308.
tophagy receptor. Aging Cell 18, e12860. https://doi.org/10.1111/acel.12860. https://doi.org/10.3389/fnagi.2017.00308.
Webb, J.L., Ravikumar, B., Atkins, J., Skepper, J.N., and Rubinsztein, D.C. Xu, Y., Propson, N.E., Du, S., Xiong, W., and Zheng, H. (2021). Autophagy defi-
(2003). Alpha-synuclein is degraded by both autophagy and the proteasome. ciency modulates microglial lipid homeostasis and aggravates tau pathology
J. Biol. Chem. 278, 25009–25013. https://doi.org/10.1074/jbc.M300227200. and spreading. Proc. Natl. Acad. Sci. USA 118, e2023418118. https://doi.
org/10.1073/pnas.2023418118.
Webster, C.P., Smith, E.F., Bauer, C.S., Moller, A., Hautbergue, G.M., Fer-
raiuolo, L., Myszczynska, M.A., Higginbottom, A., Walsh, M.J., Whitworth,
Xu, Y., Zhang, S., and Zheng, H. (2019). The cargo receptor SQSTM1 amelio-
A.J., et al. (2016). The C9orf72 protein interacts with Rab1a and the ULK1 com-
rates neurofibrillary tangle pathology and spreading through selective target-
plex to regulate initiation of autophagy. EMBO J 35, 1656–1676. https://doi.
ing of pathological MAPT (microtubule associated protein tau). Autophagy
org/10.15252/embj.201694401.
15, 583–598. https://doi.org/10.1080/15548627.2018.1532258.
Wen, X., Westergard, T., Pasinelli, P., and Trotti, D. (2017). Pathogenic deter-
minants and mechanisms of ALS/FTD linked to hexanucleotide repeat expan- Yamaguchi, H., Honda, S., Torii, S., Shimizu, K., Katoh, K., Miyake, K., Miyake,
sions in the C9orf72 gene. Neurosci. Lett. 636, 16–26. https://doi.org/10.1016/ N., Fujikake, N., Sakurai, H.T., Arakawa, S., and Shimizu, S. (2020). Wipi3 is
j.neulet.2016.09.007. essential for alternative autophagy and its loss causes neurodegeneration.
Nat. Commun. 11, 5311. https://doi.org/10.1038/s41467-020-18892-w.
Wesseling, H., Mair, W., Kumar, M., Schlaffner, C.N., Tang, S., Beerepoot, P.,
Fatou, B., Guise, A.J., Cheng, L., Takeda, S., et al. (2020). Tau PTM profiles Yamaguchi, J., Suzuki, C., Nanao, T., Kakuta, S., Ozawa, K., Tanida, I., Saitoh,
identify patient heterogeneity and stages of Alzheimer’s disease. Cell 183, T., Sunabori, T., Komatsu, M., Tanaka, K., et al. (2018). Atg9a deficiency
1699–1713.e13. https://doi.org/10.1016/j.cell.2020.10.029. causes axon-specific lesions including neuronal circuit dysgenesis. Auto-
phagy 14, 764–777. https://doi.org/10.1080/15548627.2017.1314897.
, E., Geisinger, J., Hajduskova, M.,
Wilhelm, T., Byrne, J., Medina, R., Kolundzic
Tursun, B., and Richly, H. (2017). Neuronal inhibition of the autophagy nucle- Yan, J., Porch, M.W., Court-Vazquez, B., Bennett, M.V.L., and Zukin, R.S.
ation complex extends lifespan in post-reproductive C. elegans. Genes Dev (2018). Activation of autophagy rescues synaptic and cognitive deficits in frag-
31, 1561–1572. https://doi.org/10.1101/135178. ile X mice. Proc. Natl. Acad. Sci. USA 115, E9707–E9716. https://doi.org/10.
1073/pnas.1808247115.
Winslow, A.R., Chen, C.W., Corrochano, S., Acevedo-Arozena, A., Gordon,
D.E., Peden, A.A., Lichtenberg, M., Menzies, F.M., Ravikumar, B., Imarisio, Yang, M., Chen, P., Liu, J., Zhu, S., Kroemer, G., Klionsky, D.J., Lotze, M.T.,
S., et al. (2010). a-synuclein impairs macroautophagy: implications for Parkin- Zeh, H.J., Kang, R., and Tang, D. (2019). Clockophagy is a novel selective
son’s disease. J. Cell Biol. 190, 1023–1037. https://doi.org/10.1083/jcb. autophagy process favoring ferroptosis. Sci. Adv. 5, eaaw2238. https://doi.
201003122. org/10.1126/sciadv.aaw2238.
Wolfe, D.M., Lee, J.H., Kumar, A., Lee, S., Orenstein, S.J., and Nixon, R.A. Yang, Q., She, H., Gearing, M., Colla, E., Lee, M., Shacka, J.J., and Mao, Z.
(2013). Autophagy failure in Alzheimer’s disease and the role of defective lyso- (2009). Regulation of neuronal survival factor MEF2D by chaperone-mediated
somal acidification. Eur. J. Neurosci. 37, 1949–1961. https://doi.org/10.1111/ autophagy. Science 323, 124–127. https://doi.org/10.1126/science.1166088.
ejn.12169.
Yang, Y., Hentati, A., Deng, H.X., Dabbagh, O., Sasaki, T., Hirano, M., Hung,
Wong, Y.C., and Holzbaur, E.L. (2014a). Optineurin is an autophagy receptor W.Y., Ouahchi, K., Yan, J., Azim, A.C., et al. (2001). The gene encoding alsin,
for damaged mitochondria in parkin-mediated mitophagy that is disrupted a protein with three guanine-nucleotide exchange factor domains, is mutated
by an ALS-linked mutation. Proc. Natl. Acad. Sci. USA 111, E4439–E4448. in a form of recessive amyotrophic lateral sclerosis. Nat. Genet. 29, 160–165.
https://doi.org/10.1073/pnas.1405752111. https://doi.org/10.1038/ng1001-160.
Wong, Y.C., and Holzbaur, E.L. (2014b). The regulation of autophagosome dy-
Yao, P.J., Eren, E., Petralia, R.S., Gu, J.W., Wang, Y.X., and Kapogiannis, D.
namics by huntingtin and HAP1 is disrupted by expression of mutant hunting-
(2020). Mitochondrial protrusions in neuronal cells. iScience 23, 101514.
tin, leading to defective cargo degradation. J. Neurosci. 34, 1293–1305.
https://doi.org/10.1016/j.isci.2020.101514.
https://doi.org/10.1523/JNEUROSCI.1870-13.2014.
Wu, A.G., Zhou, X.G., Qiao, G., Yu, L., Tang, Y., Yan, L., Qiu, W.Q., Pan, R., Yu, Yin, Z., Popelka, H., Lei, Y., Yang, Y., and Klionsky, D.J. (2020). The roles of
C.L., Law, B.Y., et al. (2021). Targeting microglial autophagic degradation in ubiquitin in mediating autophagy. Cells 9, 2025. https://doi.org/10.3390/
NLRP3 inflammasome-mediated neurodegenerative diseases. Ageing Res. cells9092025.
Rev. 65, 101202. https://doi.org/10.1016/j.arr.2020.101202.
Yu, W.H., Kumar, A., Peterhoff, C., Shapiro Kulnane, L., Uchiyama, Y., Lamb,
Wu, J.J., Cai, A., Greenslade, J.E., Higgins, N.R., Fan, C., Le, N.T.T., Tatman, B.T., Cuervo, A.M., and Nixon, R.A. (2004). Autophagic vacuoles are enriched
M., Whiteley, A.M., Prado, M.A., Dieriks, B.V., et al. (2020). ALS/FTD mutations in amyloid precursor protein-secretase activities: implications for beta-amy-
in UBQLN2 impede autophagy by reducing autophagosome acidification loid peptide over-production and localization in Alzheimer’s disease. Int. J.
through loss of function. Proc. Natl. Acad. Sci. USA 117, 15230–15241. Biochem. Cell Biol. 36, 2531–2540. https://doi.org/10.1016/j.biocel.2004.
https://doi.org/10.1073/pnas.1917371117. 05.010.
Wu, Z., Geng, Y., Lu, X., Shi, Y., Wu, G., Zhang, M., Shan, B., Pan, H., and Zavodszky, E., Seaman, M.N., Moreau, K., Jimenez-Sanchez, M., Breusegem,
Yuan, J. (2019). Chaperone-mediated autophagy is involved in the execution S.Y., Harbour, M.E., and Rubinsztein, D.C. (2014). Mutation in VPS35 associ-
of ferroptosis. Proc. Natl. Acad. Sci. USA 116, 2996–3005. https://doi.org/ ated with Parkinson’s disease impairs WASH complex association and inhibits
10.1073/pnas.1819728116. autophagy. Nat. Commun. 5, 3828. https://doi.org/10.1038/ncomms4828.
Xia, Q., Wang, H., Hao, Z., Fu, C., Hu, Q., Gao, F., Ren, H., Chen, D., Han, J., Zhang, X.L., Garbett, K., Veeraraghavalu, K., Wilburn, B., Gilmore, R., Mirnics,
Ying, Z., and Wang, G. (2016). TDP-43 loss of function increases TFEB activity K., and Sisodia, S.S. (2012). A role for presenilins in autophagy revisited:
and blocks autophagosome-lysosome fusion. EMBO J 35, 121–142. https:// normal acidification of lysosomes in cells lacking PSEN1 and PSEN2.
doi.org/10.15252/embj.201591998. J. Neurosci. 32, 8633–8648. https://doi.org/10.1523/Jneurosci.0556-12.2012.
Neuron 110, March 16, 2022 965

ll
Review
Zhao, Y.G., Sun, L., Miao, G., Ji, C., Zhao, H., Sun, H., Miao, L., Yoshii, S.R., dysregulation contributes to ApoE4-associated cognitive deficits in Alz-
Mizushima, N., Wang, X., and Zhang, H. (2015). The autophagy gene Wdr45/ heimer’s disease pathogenesis. Proc. Natl. Acad. Sci. USA 112, 11965–
Wipi4 regulates learning and memory function and axonal homeostasis. Auto- 11970. https://doi.org/10.1073/pnas.1510011112.
phagy 11, 881–890. https://doi.org/10.1080/15548627.2015.1047127.
Zheng, J., and Conrad, M. (2020). The metabolic underpinnings of ferroptosis. Zimprich, A., Benet-Pagès, A., Struhal, W., Graf, E., Eck, S.H., Offman, M.N.,
Cell Metab 32, 920–937. https://doi.org/10.1016/j.cmet.2020.10.011. Haubenberger, D., Spielberger, S., Schulte, E.C., Lichtner, P., et al. (2011). A
mutation in VPS35, encoding a subunit of the retromer complex, causes
Zhu, L., Zhong, M.H., Elder, G.A., Sano, M., Holtzman, D.M., Gandy, S., Car- late-onset Parkinson disease. Am. J. Hum. Genet. 89, 168–175. https://doi.
dozo, C., Haroutunian, V., Robakis, N.K., and Cai, D.M. (2015). Phospholipid org/10.1016/j.ajhg.2011.06.008.
966 Neuron 110, March 16, 2022

2022 Fleming autofagia

Uploaded by

Copyright:

Available Formats

2022 Fleming autofagia

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

2022 Fleming autofagia

Uploaded by

Copyright:

Available Formats

ll

Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK

Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK

Cambridge CB2 0AH, UK

*Correspondence: [email protected] (A.M.C.), [email protected] (D.C.R.)

Neuron 110, March 16, 2022 ª 2022 Elsevier Inc. 935

(legend on next page)

936 Neuron 110, March 16, 2022

Figure 1. Schematic representation of macroautophagy

Neuron 110, March 16, 2022 937

938 Neuron 110, March 16, 2022

Neuron 110, March 16, 2022 939

Different types of autophagy, although

940 Neuron 110, March 16, 2022

Neuron 110, March 16, 2022 941

942 Neuron 110, March 16, 2022

Neuron 110, March 16, 2022 943

Aging summarizes a more comprehensive, although not exhaustive,

944 Neuron 110, March 16, 2022

leading to disrupted degradation of SOD1 and TDP-43 (Gal

downstream of FAM134B during ER-phagy

autophagosome formation (Liu et al., 2021)

(Liang et al., 2018); impaired association

with GABARAP and impaired ER-phagy

ULK1 complex to ER-specific site of

Impaired mitophagy (reviewed in Ge

Impaired mitophagy (reviewed in Ge

Depletion inhibits ER-phagy, acts

through direct disruption of the association of ATL3 with

GABARAP (Chen et al., 2019).

Mutations in genes involved in autophagosome

ER-phagy receptor/autophagy initiation

trafficking, maturation, and fusion with lysosomes

Autophagosomes generated in axons rely on retrograde trans-

crotubules and is the target of mutations causing axonal Char-

(Puls et al., 2003). Defects in trafficking have also been associ-

ated with disease-causing mutations in a-synuclein (PD),

C9ORF72 (ALS), and with hyperphosphorylated tau (seen in

coding the late endosomal RAB7A protein, cause Charcot-

hereditary sensory and autonomic

Marie-Tooth type 2B disease (Verhoeven et al., 2003). Similarly,

recessive ALS (Yang et al., 2001). ALS can be also caused by

Parkinson disease (PD)

mutations in CHMP2B, one of the subunits of the ESCRT-III

complex, which impair autophagosome maturation (Filimo-

Mutations in genes involved in lysosomal function

tophagic cargo and subsequent release of recycled metabolites.

which is mediated by vacuolar ATPase (vATPase). Mutations in

genes associated with familial forms of neurodegeneration,

such as PSEN1 (AD) (Lee et al., 2010), a-synuclein (Decressac

et al., 2012) affect lysosomal pH. Following autolysosome fusion

hereditary spastic paraplegia, have been implicated in this pro-

cess and loss of SPG11 or SPG15 result in the depletion of lyso-

948 Neuron 110, March 16, 2022

Neuron 110, March 16, 2022 949

Table 2. Mutations in neurodegeneration-related genes with impact on CMA

950 Neuron 110, March 16, 2022

Familial AD and genetic risk factors Parkinson disease

Neuron 110, March 16, 2022 951

952 Neuron 110, March 16, 2022