Manuscript 3

Ageing Research Reviews 74 (2022) 101554
Contents lists available at ScienceDirect
Ageing Research Reviews

journal homepage: www.elsevier.com/locate/arr
Review
Roles of clock genes in the pathogenesis of Parkinson’s disease

Anastasiia Dmytrivna Shkodina a, Shing Cheng Tan b, *, Mohammad Mehedi Hasan c,
Mai Abdelgawad d, Hitesh Chopra e, Muhammad Bilal f, Dmytro Ivanovych Boiko a,
Kateryna Anatoliivna Tarianyk a, Athanasios Alexiou g, h
a
Poltava State Medical University, Poltava 36000, Ukraine
b
UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, 56000 Cheras, Kuala Lumpur, Malaysia
c
Department of Biochemistry and Molecular Biology, Faculty of Life Science, Mawlana Bhashani Science and Technology University, Tangail 1902, Bangladesh
d
Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, Beni-Suef 62511, Egypt
e
Chitkara College of Pharmacy, Chitkara University, 140401 Punjab, India
f
College of Pharmacy, Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan
g
Novel Global Community Educational Foundation, Peterlee Place NSW2700, Australia
h
AFNP Med, Haidingergasse 29, 1030 Wien, Austria
A R T I C L E I N F O A B S T R A C T
Keywords: Parkinson’s disease (PD) is a common motor disorder that has become increasingly prevalent in the ageing
Clock genes population. Recent works have suggested that circadian rhythms disruption is a common event in PD patients.
Epigenetics Clock genes regulate the circadian rhythm of biological processes in eukaryotic organisms, but their roles in PD
Genetic polymorphisms
remain unclear. Despite this, several lines of evidence point to the possibility that clock genes may have a sig
Hormonal destabilization
Mitochondrial dynamics
nificant impact on the development and progression of the disease. This review aims to consolidate recent un
Parkinson’s disease derstanding of the roles of clock genes in PD. We first summarized the findings of clock gene expression and
epigenetic analyses in PD patients and animal models. We also discussed the potential contributory role of clock
gene variants in the development of PD and/or its symptoms. We further reviewed the mechanisms by which
clock genes affect mitochondrial dynamics as well as the rhythmic synthesis and secretion of endocrine hor
mones, the impairment of which may contribute to the development of PD. Finally, we discussed the limitations
of the currently available studies, and suggested future potential studies to deepen our understanding of the roles
of clock genes in PD pathogenesis.
1. Introduction disturbances, excessive secretion of saliva, and some neuropsychiatric

symptoms such as anxiety and depression also observed (Pfeiffer, 2016;
Parkinson’s disease (PD) is the second most common neurodegen Zis et al., 2015). Another hallmark of PD is the presence of Lewy body
erative disease characterized by a range of motor features such as ri inclusions composed of a protein known as α-synuclein. If not folded
gidity, bradykinesia, tremors, postural instability, speech deficits, properly, α-synuclein becomes insoluble and forms aggregates as an
impaired handwriting, and grip force (Khan et al., 2018). The most intracellular inclusions within the neuronal cell body (Lewy bodies) and
significant pathological change found in PD is the progressive loss of processes (Lewy neuritis), which contribute to the pathogenesis of the
dopaminergic neurons in the substantia nigra pars compacta (SNpc) disorder (Ma et al., 2019).
(Surmeier, 2018). Normally, dopaminergic neurons are responsible for In recent years, the role of circadian rhythms in PD has become
transmitting dopamine to the striatum and other basal ganglia nucleus. increasingly apparent (Li et al., 2017b). Aberrations in the circadian
However, when at least 50–60% of these neurons are degenerated, the rhythms have been frequently reported in PD patients as well as
dopamine in the basal ganglia becomes depleted and this can lead to the experimental models of the disorder, which suggest that they may play
classical motor symptoms of PD (Maiti et al., 2017; Wegrzynowicz et al., an important role in PD. Circadian rhythms are managed by a molecular
2019). Besides motor symptoms, some patients also experience various clock within the suprachiasmatic nucleus (SCN), residing in the anterior
non-motor features such as olfactory deficits, visual abnormalities, sleep part of hypothalamus, which is entrained by the dark-light cycle. The
* Corresponding author.
E-mail addresses: [email protected], [email protected] (S.C. Tan).
https://doi.org/10.1016/j.arr.2021.101554
Received 2 June 2021; Received in revised form 24 November 2021; Accepted 27 December 2021
Available online 30 December 2021
1568-1637/© 2021 Elsevier B.V. All rights reserved.
A.D. Shkodina et al. Ageing Research Reviews 74 (2022) 101554
molecular clockwork consists of different core clock genes such as (Ball et al., 2019).
circadian locomotor output cycles kaput protein (CLOCK), brain and muscle A positive correlation between exposure to pesticide and PD has also
ARNT-like 1 (BMAL1), period circadian regulators 1 and 2 (PER1 and been documented, although the specific molecules responsible for this
PER2), and cryptochrome circadian regulators 1 and 2 (CRY1 and CRY2), observation as well as the molecular mechanisms involved have not
These genes are organized in a transcription-translation feedback loop been fully elucidated. It is, however, known that pesticides are able to
that oscillates every 24 h (Caba et al., 2018; Takahashi, 2017). While destroy neurons that are responsible for producing dopamine, which
initial studies suggest the association between PD and clock genes, their may explain their correlation with PD pathogenesis (Goldman et al.,
mechanistic link is not fully understood yet. In the current review, we 2017). For example, dieldrin, which is a neurotoxin pesticide, has been
summarize the recent understanding of the role of clock genes in PD, found to contribute to a higher risk of PD in a dose-dependent manner
emphasizing on the relationship between the altered clock genes via impairment of the dopaminergic neurons and consequently alter
expression as well as their genetic polymorphisms and the disorders; and ation in the entire CNS. Similarly, rotenone also elevates the risk of PD
how clock genes are linked to the regulation of mitochondrial dynamics by facilitating the accumulation of alpha-synuclein protein (Ball et al.,
and hormonal destabilization in PD. 2019). Another pesticide, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri
dine (MPTP), is converted by astrocytes to 1-methyl-4-phenylpyridium
2. Parkinson’s disease (MPP+) in the brain, where it targets the substantia nigra and conse
quently enhances the PD risk (Ball et al., 2019). Thus, many individuals
PD is a complex progressive neurodegenerative disease characterized who have been exposed to MPTP exhibit advanced PD stage, and it is for
by a generalized slowing of movements and resting tremor or rigidity this reason that several animal models of PD are generated by treating
(Balestrino and Schapira, 2020). The exact causative agent is still un the animals with this pesticide (Ball et al., 2019). Evidence for the role of
known. It is frequently thought to be an age-related disorder. However, pesticides in PD pathogenesis is further strengthened in the Geo
it has been firmly established by now that the influence of genetic sus parkinson study conducted by Dick et al. on the Malta, Romania, Swe
ceptibility and environmental factors cannot be neglected. For example, den, Italy and Scotland populations (Dick et al., 2007), where it was
a meta-analysis showed that having a family history of PD increases the noted that individuals working in sectors in which exposure to pesticides
risk of developing the disorder by 3–4 times, which reflects the contri and trace elements were frequent had an increased risk for the devel
bution of genetic factors in the PD development (Noyce et al., 2012). In opment of PD. This suggests that the exposure to pesticides may be a
fact, genetic variations represent almost 25% of the total PD risk factors, causative or potentially modifiable risk factor for PD. Many other life
and can be classified into low penetrance (e.g. MAPT, GCH1, GAK, BST1, style factors, such as consumption of the well water, poor living standard
HLA, DRB5, SYT11 and some SNCA variants), moderate penetrance (e.g. and employment in the agricultural sector, have also been hypothesized
GBA and LRRK2 variants) or high penetrance (e.g. ATP13A2, FBX07, to contribute to PD pathogenesis. For example, a cohort study based on
PINK1, PARK7, PRKN, VSP35, and some SNCA variants) types, which the French population showed that there was an increase in PD-related
have a high, moderate and low frequency respectively. Based on the type hospital administration among people employed in the agricultural
of the causative genetic variants, PD can be divided into either mono sector (Pouchieu et al., 2018). A similar study based on the Hawaii
genic or idiopathic forms, whereby the monogenic form is caused by the population also found that plantation workers were more prone to the
rare high-penetrance variants whereas the idiopathic form is caused by development of PD (Petrovitch et al., 2002). These observations suggest
the common or moderate variants (Day and Mullin, 2021). Interestingly, that pesticide and occupational exposures could be linked to PD devel
the monogenic form may result in a distinct disease progression pattern opment, although further studies are necessary to validate the causal
compared to the idiopathic form. Notably, most laboratory PD models relationship between the above-mentioned risk factors and the disorder
have emphasized on the monogenic pathways of PD pathogenesis (Day (Gunnarsson and Bodin, 2019).
and Mullin, 2021). Monogenic PD can be further classified into either Besides pesticide and occupational exposures, a study conducted by
autosomal dominant or recessive forms, depending on the genes Fang et al. showed that there exists an inverse relationship between high
mutated. For example, SNCA mutations are found to be in close asso physical activity and the development of PD (Fang et al., 2018). Simi
ciation with the autosomal PD (Dashtipour et al., 2017; van Heesbeen larly, and perhaps surprisingly, inverse correlations between PD and
and Smidt, 2019a, 2019b). Other types of mutations or multiplications, smoking (Domínguez-Baleón et al., 2021), calcium ion blockers (Chen
such as single nucleotide polymorphisms (SNPs), can also alter the dis et al., 2021a) and statins (Chen et al., 2021a) have been consistently
ease risk by manipulating the gene expression (Langmyhr et al., 2021; reported. In addition, the administration of β2-antagonists has been
Maszlag-Török et al., 2021; Tan et al., 2021; Usenko et al., 2021). In found to lead to an increase in the incidence of PD, while β2-agonists
Caucasian or Asian populations, for instance, the rs35621, rs356165, tend to decrease the risk of PD (Mittal et al., 2017).
rs11931074 and rs7684318 polymorphisms, among others, had been Today, while there is no holistic technique for early diagnosis and
found to be linked to a higher risk of PD (Shu et al., 2018). Recent studies prognostication of PD, clinicians often apply a combination of tests and
have also shown that shortening of telomeres, as a result of their biomarkers to identify the potential PD development and its outcomes
inability to replicate the ends of linear chromosomes, also leads to PD (Li and Le, 2019) (Fig. 1). Nonetheless, PD patients are commonly pre
pathology (Wu et al., 2020). sented with motor symptoms, such as tremor, rigidity, bradykinesia and
Genetic factors interact with various environmental risk factors to postural instability, although it is now known that PD has a prodromal
result in the final phenotype (Álvarez-Castro, 2020). Therefore, both phase prior to the onset of the motor symptoms (Khan et al., 2018; Rees
factors should be considered in terms of disease diagnosis, treatment, et al., 2019). The motor symptoms of PD are typically attributed to the
and laboratory study. For instance, caffeine consumption is known to loss of dopaminergic neurons in the SNpc and the Lewy body deposition
decrease PD risk by working as an adenosine A2A receptor antagonist to in the midbrain that may occur due to toxins, drugs, pesticides, brain
enhance dopamine neurotransmission, although the risk can be miti microtrauma, genomic defects, etc (Naughton et al., 2017; Ritz et al.,
gated by polymorphisms in the adenosine A2A receptor gene (Chuang 2016; Shrestha et al., 2020). The loss of dopaminergic neurons causes
et al., 2016; Palacios et al., 2012; Popat et al., 2011), On the contrary, variations to the dopamine content, whose rhythmic release can be
exposure to heavy metals such as iron, copper, manganese and lead regulated by the circadian clock (Mendoza and Challet, 2014). In
increases PD risk by causing genetic alterations to the genes involved in addition, changes in rate of synthesis of tyrosine hydroxylase, which is
PD pathogenesis, such as LRRK2, PARK1, and PINK1. Some heavy metals one of the major rate limiting enzymes in the dopamine synthesis, as
are also considered to be brain neurotoxins, which cause oxidative well as dopamine transporters may also be observed, and these processes
stress, neuronal damage particularly mitochondrial damage, and are known to be regulated by clock genes (Lauretti and Praticò, 2020).
neurotransmission impairment with dramatic effects in basal ganglia Besides motor symptoms, PD patients are also commonly present
2
several studies have established a link between photoentrainment and

altered clock genes expression (Bluhm et al., 2012; Farhat et al., 2009;
Lax et al., 2019; Ruan et al., 2012). Disrupted photoentrainment (and
therefore clock gene regulation) can be clinically examined by using
methods such as pupillometry, which can differentiate retinal affection
in the inner and outer retina as seen in PD patients. In addition,
pupillometry is useful for indicating circadian synchronization in the
elderly, autonomic dysfunction and disease stage in PD (Giza et al.,
2011; Novotny and Plischke, 2017; You et al., 2021). Apart from that,
many of the non-motor symptoms mentioned above, such as mood dis
order and cognitive changes, are also linked to clock genes (Bolsius
et al., 2021; Schuch et al., 2018). These observations highlight the
important roles of clock genes in the pathogenesis of PD.
The gold standard treatment for PD is levodopa (L-Dopa) (Lee,
2019). L-Dopa has the ability to cross the blood brain barrier, making it a
strong candidate for PD treatment. Moreover, L-Dopa is the precursor of
dopamine, thus it can directly increase the concentration of dopamine
inside the brain (Haddad et al., 2018). In the initial stages, L-Dopa
administration had shown profound effects on improving motor-related
symptoms. It is now known that L-Dopa may also increase the lifespan of
PD patients (Morgan et al., 2014). However, L-Dopa has been reported
to speed up the process of neuronal degeneration through oxidative
metabolism, which can result in dyskinesia (Jankovic et al., 2015;
Pandey and Srivanitchapoom, 2017). Thus, although the administration
of L-Dopa may halt the disease progression, its long term use may result
in negative effects.
Apart from L-Dopa, dopaminergic agonists (DAs), anticholinergic
drugs, monoamine oxidase inhibitors (MAOIs) and catechol-O-
methyltransferase inhibitors (COMTIs) are also used in the treatment
of PD. DAs such as pergolide and ropinirole can directly stimulate the
postsynaptic DA receptors and, along with L-Dopa, they can help in
delaying the onset of motor fluctuations (BROOKS, 2000). However,
Fig. 1. A proposed PD Decision Support System for the early diagnosis and they are more expensive in comparison to L-Dopa and can cause side
efficient assessment of the disease. effects such as sleeping disorders, hallucinations and cognitive prob
lems. On the other hand, anticholinergic drugs such as benztropine and
with non-motor symptoms, such as mood disorders, dizziness, sexual trihexyphenidyl function by blocking the muscarinic receptors near to
problems, cognitive changes, sleep disorders and visual disorders. Sleep the striatal interneurons (Lester et al., 2010). They have been shown to
and visual disorders are, in fact, among the earliest non-motor symp reduce tremors but are also known to cause many side effects such as
toms found in PD patients. Sleep disorders could be observed in patients cognitive impairment, confusion, and hallucinations. Besides, MAOIs
even before the diagnosis of PD, but become more frequent and severe as such as selegiline and rasagiline also showed anti-PD effect (Cereda
the disease progresses (Bohnen and Hu, 2019; Melka et al., 2019; et al., 2017; Finberg, 2020; Szökő et al., 2018; Tábi et al., 2020). They
Zesiewicz and Hauser, 2007). Sleep is directed by the complex interplay are generally more effective in patients with moderately advanced PD
between sleep-wake homeostasis and circadian rhythms in the body, suffering from levodopa related motor complications.
which are regulated by clock genes (Dijk and Landolt, 2019). Catechol-O-methyltransferase inhibitors (COMTIs) act by blocking the
Normally, humans have a robust 24-hour circadian rhythm in sleep degradation of peripheral levodopa and increasing the central L-Dopa
desire that is controlled by the SCN in response to light signals from the and dopamine levels (Khan et al., 2021). However, hepatotoxicity has
retinal cells throughout the day and melatonin release from the pineal been reported with their use. Their primary role is to prolong the effect
gland during the night (Gentry et al., 2021). In PD patients, however, the of L-Dopa and therefore can be used as an adjunctive therapy in patients
SCN activity is reduced, which results in elimination of the rhythmic with reported motor fluctuations. Apart from that, non-conventional
secretion of melatonin or other hormones related to clock gene that lead therapies, such as administration of Berberine, may ameliorate PD
to sleep-wake disruptions (French and Muthusamy, 2016). These dis symptoms by facilitating the conversion of L-Dopa produced by intes
ruptions include increased sleep latency, reduced sleep efficiency, and tinal bacteria into dopamine (Wang et al., 2021). Similarly, the use of
reduced rapid eye movement sleep (Keir and Breen, 2019). Visual dis L-Dopa nanocarriers, such as the self-assembled nano-L-Dopa (Nano
orders, on the other hand, occur when PD patients suffer from retinal DOPA
), also increased the dopamine levels and at the same time,
damage as a result of aging, synucleinopathy and melanopsin system decreased the incidence of dyskinesia symptoms that are commonly
dysfunction. These cause a decrease in the number of observed when L-Dopa is given through other routes or modes (Vong
melanopsin-containing retinal ganglion cells (RGCs) in PD patients, et al., 2020). Other treatments, such as the administration of intrave
which is accompanied by a decrease in the complexity of their network nous dopamine and PT-320, are also promising options for PD treatment
and morphological changes. Dysfunction in the photosensitive RGSs in (Moreau et al., 2020; Yu et al., 2020).
the inner retinal is also linked to poor sleep quality in PD patients (Feigl
et al., 2020). Besides, dopaminergic neurons of the retina form synapses 3. Epigenetic regulation in Parkinson’s disease
with melanopsin-containing RGCs, which mediate circadian photo
entrainment in response to environmental light. Thus, circadian Apart from genetic alterations mentioned above, epigenetic modifi
dysfunction in PD is commonly linked to an altered dopaminergic cations are also commonly observed in PD. Epigenetics refers to alter
modulation of melanopsin cells. In the modern society, clock disruption ation in the expression or function of specific DNA loci without any
is often associated with photoentrainment (Xie et al., 2019). In fact, change in the sequence itself. When epigenetic modifications occur in
3
PD-related genes, a change in expression levels of the genes, and genes involved in PD pathogenesis (Singh and Sen, 2017), while
consequently their protein products, happens, and can lead to PD miR-34b and miR-34c have been found to be associated with a decrease
pathogenesis. in the expression of PD-associated genes, PARK2 and PARK7
Different types of epigenetic modifications have been known (Pavlou (Miñones-Moyano et al., 2011; Villar-Menéndez et al., 2014). Apart
and Outeiro, 2017; van Heesbeen and Smidt, 2019a, 2019b). The main from that, profiling of the levels of miRNAs in human subjects also
epigenetic modification is DNA methylation which involves the addition revealed a downregulation of miR-124 (Kanagaraj et al., 2014),
of a methyl group to a particular amino acid (cytosine) in the CpG miR-34b, miR-34c (Miñones-Moyano et al., 2011), miR-133b (Kim et al.,
islands (Pavlou and Outeiro, 2017). DNA methylation is responsible for 2007), miR-22, miR-1, and miR-29 (Margis et al., 2011) in PD patients;
switching (on and off) of genes leading to the control and regulation of as well as an upregulation of hsa-miR-4639–5p (Chen et al., 2017),
their expression levels. In PD, methylation of the synuclein alpha (SNCA) miR-373, miR-224, and miR-21 (Alvarez-Erviti et al., 2013), miR-1826,
gene has been frequently investigated as it is among the most important miR-450b-3p, and miR-505 (Khoo et al., 2012). An alteration in the
genes involved in the disorder (Guhathakurta et al., 2017). Despite this, levels of miR-10b, miR-10a, miR-212, miR-132, and miR-495 has also
the findings have been inconclusive (Pavlou et al., 2017). On one hand, been found in PD patients (Gillardon et al., 2008), indicating the po
it has been shown that the hypomethylation or demethylation of intron 1 tential role of miRNAs in the development of PD.
CpG island was correlated to a high level of SNCA expression, which was Gene expression is also epigenetically regulated by a complex pro
in turn associated with the incidence of PD (Jowaed et al., 2010; Mat cess known as chromatin remodeling, which includes various types of
sumoto et al., 2010). This observation could be attributed to the low histone modifications such as phosphorylation, ubiquitination, acety
level of the Dnmt1 protein, which is responsible for DNA methylation lation, SUMOylation, hydroxylation, and other posttranslational modi
maintenance (Desplats et al., 2011). When the expression of SNCA is fications (Bandres-Ciga et al., 2020; Rathore et al., 2021). These
high, sequestration of Dnmt1 occurs in the cytoplasm, which subse modifications are known to play a substantial role in the dopaminergic
quently decreases the expression level of the former via hypo neuron differentiation and development, although their role in PD
methylation (Desplats et al., 2011). In addition to SNCA, Dnmt1 pathogenesis is still unclear since little information is available (van
retention has also been linked to hypomethylation of the selenoprotein W Heesbeen et al., 2013). Nevertheless, it has been observed that changes
(SEPW1) and cAMP-dependent protein kinase type II regulatory subunit in histone acetylation, usually at the H2A, H3, and H4 subunits, are
alpha (PRKAR2A) genes (Desplats et al., 2011). Nevertheless, on the common in the dopaminergic neurons of the midbrain of PD patients
other hand, next-generation sequencing data showed that hyper (Park et al., 2016). In fact, α-synuclein, which often accumulates in Lewy
methylation of SNCA intron 1 and promoter region was observed in PD bodies and neurites, is known to suppress H3 histone acetylation by
patients in comparison to controls (De Boni et al., 2011). Apart from interacting with sirtuin-2 deacetylase (Liu et al., 2020b). In addition, H3
that, a study indicated no change in the methylation level of SNCA gene histone modification has been shown to regulate the level of the
in PD patients compared to control in the leukocyte samples via exam microtubule-associated protein tau (MAPT) (Renani et al., 2019).
ination of the methylation level of 13 CpG islands located in SNCA intron
(Song et al., 2014). More studies are therefore needed to elucidate the 4. Clock genes
role of SCNA methylation in the pathogenesis of PD.
In addition of SCNA, methylation in many other genes has been Almost all organisms possess a cell-autonomous circadian clock
investigated with regard to their association with PD. For example, the which generates and maintains a 24-hour oscillation in physiological
glycoprotein NMB (GPNMB), Parkinson’s disease 16 (PARK16) and syn processes (Cox and Takahashi, 2019). Central to the circadian clock is a
taxin-1B (STX1B) genes have been shown to exhibit irregular methyl set of genes, collectively known as the ‘clock genes’, which encode
ation in the PD brain samples after postmortem examination various transcription factors that rhythmically regulate the expression of
(International Parkinson’s Disease Genomics Consortium (IPDGC) and downstream genes (Cox and Takahashi, 2019). Some of the key clock
Wellcome Trust Case Control Consortium 2 (WTCCC2), 2011). Likewise, genes include the CLOCK at chromosome 4q12 in humans, BMAL1 at
Fanconi anemia group C (FANCC) and tankyrase 2 (TNKS2) displayed chromosome 11p15.3, PER1 and PER2 at chromosomes 17p13.1 and
irregular methylation levels (Weis et al., 2019), while similarly, hyper 2q37.3 respectively, and CRY1 and CRY2 at chromosomes 12q23.3 and
methylation was demonstrated in peroxisome proliferator-activated re 11p11.2 respectively. In addition to regulating the downstream targets,
ceptor gamma coactivator 1-alpha (PGC1A) (Piccinin et al., 2021). A study the protein products of these genes are known to interact, and form an
done by Malish et al. showed hypermethylation of the following genes in autoregulatory loop, with one another (Takahashi, 2017).
PD: HLA-DQA1, TMEM9, MOG, TRIM10, GFPT 2, KCTD5, HLA-DRB5, The CLOCK gene, whose protein product possesses histone acetyl
VAV2, MRI1, MAPT, HLA-DRB6, LASS3, GSTTP2, ARHGEF10 and transferase (HAT) activity, is known to be constitutively expressed at
GSTTP1 (Masliah et al., 2013). Apart from that, hypomethylation was both transcriptional and translational levels. Several alternatively
observed in the following genes: MAGI2, FOXK1, DNAJA3, JAKMIP 3, spliced variants of CLOCK have been identified, although the function of
DMBX1, SLC25A24, GSTT1, LRRC27, LGALS7, MYOM2, TUBA3E, these splice variants remains poorly understood (Crosby and Partch,
APBA1, TMCO3, FRK and MIR886 (Masliah et al., 2013). In addition, 2020). The Clock protein contains two Per-Arnt-Sim (PAS) domains,
epigenome-wide association studies have also identified irregular DNA through which it heterodimerizes with Bmal1 in the cytoplasm (Fig. 2).
methylation in 20 genes in PD patients compared to healthy individuals This heterodimerization not only further enhances the HAT activity of
(Masliah et al., 2013; Moore et al., 2014). All these observations illus the Clock protein, but also allows the nuclear transport of the
trate the importance of DNA methylation in PD. Clock-Bmal1 complex. In the nucleus, the heterodimer binds to the
Another epigenetic modulator that controls the gene expression is enhancer boxes (E-boxes; the 5’-CACGTG-3’ and 5’-CACGTT-3’ se
the microRNAs (miRNAs), which are short (18–22 nucleotides) non- quences) of the downstream genes and decondenses their chromatin to
coding RNAs that inhibit gene expression by binding complementarily allow the access of the gene transcription machinery (Cao et al., 2021;
to the target mRNAs to achieve transcription suppression and/or Freeman et al., 2019). Apart from catalyzing the acetylation of histones,
degradation of the mRNA transcripts (Arshad et al., 2017; Fyfe, 2019). A the Clock-Bmal1 heterodimer also recruits the transcriptional coac
number of miRNAs have been shown to contribute to PD through the tivators such as mixed lineage leukemia protein-1 (MLL1) and histone
alteration of gene expressions. For instance, miR7 and miR-153 together deacetylase inhibitors such as Jumonji, AT-rich interactive domain 1
control and regulate α-synuclein expression (Singh and Sen, 2017; (JARID1A) to facilitate the promotion of downstream gene expression
Titze-de-Almeida et al., 2020), while miR-106a increases its expression (Rosensweig and Green, 2020).
(Zhao et al., 2019). In addition, miR-205 has been reported to be a Among the downstream genes activated by the Clock-Bmal1 heter
regulator of leucine-rich repeat kinase 2 (LRRK2) which is one of the key odimer are the PER and CRY genes mentioned above. When PER and
4
Fig. 2. Interrelationship among the clock genes. (1) CLOCK and BMAL1 encode Clock and Bmal1 respectively. (2) Clock and Bmal1 form heterodimer with each
other. (3) The Clock-Bmal1 heterodimer reenters the nucleus to facilitate the transcription of PER and CRY. (4) PER and CRY encode Per and Cry respectively. (5) Per
and Cry form heterodimer with each other. (6) The Per-Cry heterodimer reenters the nucleus to inhibit the transcription of CLOCK and BMAL1.
CRY are expressed abundantly, their protein products, too, form heter regulates the expression of genes encoding nuclear receptors (REV-ERBα
odimers, which subsequently re-enter the nucleus to inhibit the Clock- and REV-ERBβ), and retinoic acid-related orphan receptors (RORα and
Bmal1 complex, thus forming an autoregulatory feedback circuit RORβ) (Angelousi et al., 2018). These receptors compete for the ROR
(Takahashi, 2016) (Fig. 2). Inhibition of the Clock-Bmal1 complex by binding site on BMAL1 promoter, and therefore influence the expression
Per-Cry heterodimers can occur via multiple mechanisms, including of the latter. Specifically, Ror activates the expression of BMAL1,
causing conformational changes to the former as well as promoting whereas Rev-Erb represses it, which in turn inhibits the function of the
phosphorylation (Saini et al., 2019). In addition, Per is also known to Clock protein. Thus, these genes together form a secondary regulatory
regulate the recruitment of Sin3-histone deacetylase complex to feedback loop. In addition, several other genes regulated by the
Clock-Bmal1-bound DNA to revert the acetylation status of the bound Clock-Bmal1 heterodimer include, but not limited to, arginine vasopressin
gene (Duong et al., 2011). Various combinations of Per paralogs (Per1 (AVP), which encodes a hormone that regulates osmotic balance in the
and Per2) and Cry paralogs (Cry1 and Cry2) are known to form heter bloodstream; D-site binding protein (DBP), which modulates the expres
odimers with one another (Silva and Domínguez, 2019). Nevertheless, sion of numerous circadian rhythm genes; cardiotrophin-like cytokine
the functional role of the two paralogs appears to be unequal, as mu factor 1 (CLCF1), which suppresses the locomotor activity at appropriate
tations that lead to the loss of Per1 activity were found to alter the circadian phases; and prokineticin 2 (PK2), which transmits signals from
circadian period length of the circadian clock in vivo, whereas null the suprachiasmatic nucleus to control the circadian rhythm (Finger and
mutations of PER2 caused arrhythmicity (Bae et al., 2001; Cermakian Kramer, 2021; Kraves and Weitz, 2006; Li et al., 2009; Trott and Menet,
et al., 2001). Interestingly, a decreased expression of PER1 and CRY1 2018).
was shown to respectively lead to an enhanced expression of PER2 and Mutations and alterations to the clock genes and proteins have been
CRY2, a phenomenon termed paralog compensation, but this compen shown to result in functional impacts. For example, an A-to-T mutation
satory expression was not observed when the expression of PER2 and in exon 19 of CLOCK, which leads to a 51-amino acid truncation of the
CRY2 was reduced (Baggs et al., 2009). Clock protein, was found to be correlated with abnormal and eventually
The expression of PER1 and PER2 in the SCN was also affected by loss of circadian periodicity in vivo (Gao et al., 2020). Similarly,
light, as the human circadian system uses a network of photosensitive knockdown of BMAL1 in mice was found to result in a total loss of
RGCs that express the photopigment melanopsin. Thus, light signals circadian rhythmicity. Besides, depending on the site of mutations, al
through the retino-hypothalamic pathway converge on cAMP-response terations to PER and CRY sequences can affect their intracellular local
elements in the promoters of several clock genes. It has been shown ization, mRNA degradation, and translation (Crosby and Partch, 2020;
that light at dawn advanced the clock, specifically by advancing the Lee et al., 2014). In addition, phosphorylation of Clock, Bmal1, Per and
onset of the PER1 mRNA rhythm and acutely increasing its mRNA Cry proteins through the action of casein kinase and/or other kinases
transcription; whereas light at dusk delayed the clock, specifically by also marks them for ubiquitination and subsequent proteasomal degra
delaying the offset of the PER2 mRNA rhythm and increasing mRNA dation (Hirano et al., 2016; Srikanta and Cermakian, 2020; Yoshitane
stability. There are also suggestions that the underlying molecular and Fukada, 2021). There is also emerging evidence of
mechanisms of circadian entrainment differ between morning and eve post-transcriptional modifications in clock genes, as exemplified by the
ning light exposure. Recently research in animal model showed that blue N6-methyladenosine (m6A) methylation of PER2 and BMAL1, which
light was capable of slightly modulating PER1 gene and increasing PER2 have been demonstrated to affect their nuclear transport (Preußner and
expression (Dannerfjord et al., 2021; Foster et al., 2020; Ramos et al., Heyd, 2016). Finally, the 3’-untranslated region (3’-UTR) of the clock
2014; Schwartz et al., 2011). genes has been shown to be a common binding site of numerous
Apart from PER and CRY, the Clock-Bmal1 heterodimer also microRNAs, which suggests that the level of the clock genes may be
5
regulated at the post-transcriptional level (Jiang et al., 2018; Park et al., expression in the L-Dopa-treated mice in the SCN at 4:00 ZT and 16:00
2020; Tan et al., 2012; Tang et al., 2020; Yoo et al., 2017). ZT, at 10:00 ZT in the striatum. The expression acme of PER2 came later
Clock genes are also known to play important roles in regulating cell at 16:00 ZT. This clock genes deregulation was noticed in spite of the
cycle and division. For example, Per1 is known to promote cell cycle improvement in motor function, as noted in treadmill performance (Li
arrest in response to DNA damage by regulating the expression of et al., 2017c).
checkpoint kinase 2. Similarly, in injured mice with dysfunctional CRY1 In addition to MPTP and 6-OHDA-treated mice, several gene
and CRY2, Clock/Bmal1 was found to activate the transcription of WEE1 expression studies were conducted on mice which had been induced to
whose protein product delayed the G2/M transition in mitosis. For these develop PD using lipopolysaccharides, rotenone or manganese (Deng
reasons, the loss of circadian control can result in abnormal cell growth et al., 2020; Lawana and Cannon, 2020; Pingale and Gupta, 2020). An
as well as telomere length, which implicates clock genes in diseases like example of this is a study which applied rotenone on previously sensi
cancers (Farshadi et al., 2020; Kagawa, 2012). In fact, in cancers, clock tized mice with a single injection of LPS. This did not aggravate only the
genes were found to play additional regulatory roles, such as by con animals’ motor function and the histologic features (Huang et al., 2017),
trolling the transcription of p53 pathway genes (mediated by Bmal1), or but further affected the expression of circadian machinery. When LPS
by targeting Myc oncoprotein for degradation (mediated by Cry2) and rotenone were applied, significant downregulation of CLOCK and
(Huber et al., 2016; Shostak, 2017). Besides, circadian clock also plays BMAL1 gene expression was observed, which unequivocally points out
an important role in the control of autophagy in liver cells, due in part to the significance of clock genes in the pathogenesis of PD (Li et al., 2019).
its transcriptional target genes which are involved in mitochondrial Similar results were reported in a study by Li et al., which reported
division and fusion. In fact, recent evidence shows that autophagy is significant downregulation of CLOCK and BMAL1 genes in male
under strong circadian regulation at the proteomic and Sprague-Dawley rats treated with manganese injections in the peritoneal
post-translational levels (Wang et al., 2018b). cavity (Li et al., 2017a).
Apart from that, clock genes also regulate several physiological Despite the common belief that clock genes regulate only sleep, our
processes. For example, by controlling the expression of ion channel knowledge broadened with the studies on BMAL1 -/- mice. These mice
genes in the autonomic nervous system, clock genes can affect an in did not only have altered sleep-wake patterns, but also showed a pro
dividual’s blood pressure and heart rate (Rabinovich-Nikitin et al., geria phenotype due to the accumulation of reactive oxygen species in
2021; Tong et al., 2013). In addition, by regulating the formation of the tissues (Chen et al., 2021b). BMAL1 is also known to control quotidian
brown adipose tissue which plays key functions in maintaining body trafficking to inflammatory lesions (Pick et al., 2019; Waggoner, 2020).
temperature, clock genes have been associated with the control of the A landmark study on the expression of clock genes in rotenone-induced
core body temperature (Coiffard et al., 2021). Besides, clock genes can PD in male mice reported the loss of diurnal rhythm in BMAL1, CRY1
regulate metabolic and immune responses, such as the secretion of and CRY2 expression in SCN, while the expression of PER2 gene
proinflammatory interleukins. For this reason, lifestyle changes, such as remained unaltered (Mattam and Jagota, 2015). In addition, exogenous
disturbances in the light regime, a decrease in the amplitude ambient administration of melatonin restored only the phase of PER1 expression
temperature, a shift in the time of eating, the distribution of the energy and did not affect the phase of PER2 and CRY2 expression in SCN
value of food during the day, lead to metabolic disorders and the (Mattam and Jagota, 2015). Finally, Wang et al. reported that the gen
development of low-intensity systemic inflammation (Kaidashev, 2020). eration of reactive oxygen species is mediated by the SIRT1- BMAL1
Moreover, clock-controlled transcription factors are known to have a pathway (Wang et al., 2018a). Specifically, injection of 6-OHDA in vivo
prominent role in muscle differentiation and maintenance (Li et al., and in vitro significantly downregulated the expression of CLOCK,
2021). The circadian clock also regulates basic body functions such as BMAL1 and PER2 clock genes, as well as CAT and GPX, which constitute
pulmonary capacity, sleep, and processes in the nervous tissue that parts of the cell’s antioxidant machinery. Resveratrol, a potent SIRT1
cause neurological and psychiatric diseases such as auto-aggressive agonist, decreased the levels of acetylated BMAL1 and antagonized
behavior, neuropathic pain, etc. Some studies also found an associa partially the binding of Bmal1 and Cry. These effects were induced by
tion between the development of certain symptoms and specific chro 6-OHDA (Wang et al., 2018a). Oxidative stress is proven to be a
notypes determined by the circadian rhythm, which may help to develop precipitating factor of PD.
chronotherapy and improve treatment by prescribing drugs in accor Apart from animal studies, a number of studies have examined the
dance with the patient’s circadian rhythm (Boiko et al., 2017; Burish expression of clock genes on human subjects. For example, Cai et al.
et al., 2019). observed, in samples of peripheral blood, a decrease in the expression of
BMAL1, while PER1 expression remained unchanged (Cai et al., 2010).
5. Clock gene expression in Parkinson’s disease This observation was particularly evident during low lighting conditions
at night. The decreased expression could not be attributed to L-Dopa,
In 2006, Yujnovsky et al. documented in the NG108–15 cell line that since the results were confirmed in treatment naïve patients. Interest
MAPK signaling pathway mediates the signal transduction from dopa ingly, this effect correlates with the patients’ Unified PD Rating Scale
mine receptor 2 to the Clock:Bmal1 heterodimer, potentiates its function score, making BMAL1 expression a possible predictive and prognostic
as a transcription factor (Yujnovsky et al., 2006). The group also noted biomarker (Cai et al., 2010). Ding et al. subsequently took a step further
that alterations to the Clock activity terminate the dopamine-mediated to study BMAL2, CLOCK and DEC1 genes in the patient population, and
signaling (Yujnovsky et al., 2006). Since then, the expression of clock found that BMAL2 was downregulated in a similar pattern as BMAL1,
genes has been commonly investigated in PD animal models whose but no alteration was observed for the other two genes (Ding et al.,
dopaminergic nigrostriatal neurons are intentionally damaged with 2011).
neurotoxins like MPTP and 6-hydroxydopamine (6-OHDA) to mimic the Apart from that, while investigating the sleep phenotype during a 24-
PD pathology (Chia et al., 2020). For example, Hayashi et al. experi hour time period, Breen et al. documented a linear expression of BMAL1
mented in mice treated with MPTP that exhibit both the motor and in PD patients in contrast with the oscillatory pattern of controls and a
non-motor symptoms of PD, and found that the expression of CLOCK spike in the expression of PER2 at 04:00 (David P. Breen et al., 2014).
gene remained unaltered in the course of time, in contrast with BMAL1, This study reveals important clinical and pathophysiologic clues about
PER1, PER2, CRY1, DEC1 and REV-ERBA which showed a decreased the disease (Leroy et al., 1998). In addition, Delgado-Lara et al. inves
amplitude (Hayashi et al., 2013). Taking a few steps further, Li et al. tigated the effect of melatonin supplementation on BMAL1 and PER1
investigated the potential effect of treatment with levodopa in the expression (Delgado-Lara et al., 2020). They reported an upregulation of
circadian rhythm deregulation (Li et al., 2017c). In the 6-OHDA mouse BMAL1, in contrast to the PER1 expression which was unaffected. It is
model, the researchers documented the downregulation of BMAL1 interesting that these results can be ascribed to placebo effect, a common
6
phenomenon at least to the motor phenotypes of the disease, which Table 1

enhances the dopamine secretion in the mesolimbic system (Delgado- Association of polymorphisms in clock genes with PD risk and symptoms.
Lara et al., 2020). Besides, Pacelli et al. documented an interconnection Gene Polymorphism Main findings Reference
of metabolic cellular processes with circadian rhythm machinery, using
CLOCK rs1801260 Associated with an increased risk of (Lou et al.,
fibroblasts from PD patients with the mutated PARK2 gene (Pacelli et al., PD, as well as motor fluctuation and 2018, 2017)
2019). More specifically, they reported the loss of oscillatory pattern of sleep disorder
expression in CLOCK and PER1 genes, while BMAL1 remained unaf BMAL1 rs900147 Associated with a decreased risk of (Gu et al.,
fected (Pacelli et al., 2019). PD; subgroup analysis found that the 2015)
association was significant among
A few studies also investigated the possible epigenetic link between PD patients with TD
clock genes and PD. This is exemplified by Lin et al., who investigated a PER1 rs2253820 Associated with an increased risk of (Gu et al.,
possible contribution of clock genes promoter methylation in PD’s PD; subgroup analysis found that the 2015)
pathogenesis (Lin et al., 2012). This study, which was conducted on 206 association was significant among
PD patients with PIGD
PD patients and 181 healthy controls, showed that only CRY1 and
PER2 rs2304672 No significant association (Lou et al.,
NPAS2 (the paralog of CLOCK) promoters exhibited methylation, and 2017)
only the latter was significantly hypomethylated in PD patients (Lin CRY1 rs2287161 Associated with a higher score of (Hua et al.,
et al., 2012). Nonetheless, other genes, including CLOCK, BMAL1, PER1, Hamilton Rating Scale for 2012)
PER2 and CRY2, were found to be not regulated epigenetically by DNA Depression
CRY2 rs10838524 No significant association (Hua et al.,
methylation in both cases and controls. However, another study found 2012)
the presence of DNA methylation in 7 out of 80 dementia patients in the
CpG island of the following nine clock-related genes: CK1ε, BMAL1,
CRY2, CLOCK, PER1, PER2, PER3, TIM, and CRY1, while there was no Rating Scale for Depression, whereas no association was observed for the
methylation in any of the control individuals (Liu et al., 2008). More CRY2 rs10838524 polymorphism. Despite this, the statistical signifi
over, patients having Dementia with Lewy bodies (DLB) exhibited the cance of CRY1 rs2287161 was lost when the data was adjusted for other
highest frequency (35.7%) of the methylation in the CpG island in the potential confounders, suggesting that the polymorphism could play a
circadian genes (Chouliaras et al., 2020; Liu et al., 2008). These obser limited role in the development of depression in PD.
vations suggest that DNA methylation could play some contributory role Besides, Gu et al. (2015) used a mid-throughput method to genotype
in the development of PD. 132 tag polymorphisms in eight genes involved in the clock pathway,
including CLOCK, BMAL1, PER1, CRY1, and CRY2, on 1394 individuals
6. Clock gene polymorphisms and Parkinson’s disease with PD and 1342 healthy controls. Among the 132 tag polymorphisms,
only the rs900147 of BMAL1 and rs2253820 of PER1 were significantly
Genetic polymorphisms are the most abundant source of DNA associated with a decreased and an increased risk of PD, respectively.
sequence variation in humans. Depending on the location of the poly Interestingly, when the PD cases were categorized into different sub
morphisms, they may influence the transcriptional efficacy of the gene types, statistically significant association was only observed in tremor
or the structure (and therefore, the function) of the protein product. dominant (TD) cases for BMAL1 rs900147, and in postural instability
Since dysregulated gene expression and altered protein functions are and gait difficulty (PIGD) cases for PER1 rs2253820 polymorphism. The
among the major hallmarks of many disorders, genetic polymorphisms functional impacts of these two polymorphisms are not well-understood.
have been implicated as a risk factor in many diseases, including PD However, both polymorphisms are located in the exon and/or promoter
(Pang et al., 2019; Pihlstrøm et al., 2016), Alzheimer’s disease (Carmona regions of their respective genes, and may therefore influence the
et al., 2018; Naj and Schellenberg, 2017), cerebrovascular disease transcription or the amino acid structure of the protein products (Gu
(Della-Morte et al., 2016), infectious diseases (Mozzi et al., 2018), et al., 2015).
cancers (Tan, 2018; Tan et al., 2020; Tan and Ankathil, 2015), peri More recently, Lou et al. (2017) investigated the association of
odontal and cardiovascular diseases (Aarabi et al., 2017), psoriasis CLOCK rs1801260 and PER2 rs2304672 polymorphisms with suscepti
(Capon, 2017), and virtually all genetic diseases (Timpson et al., 2018). bility to PD on a series of 646 PD cases and 352 healthy controls. The
Perturbations to the clock gene network can lead to irregularities in CLOCK rs1801260 polymorphism was previously found to lead to a
circadian rhythm and have been associated with metabolic dysfunction, higher expression level of the gene (Ozburn et al., 2016), although this
oxidative stress and inflammatory abnormalities, which may contribute finding needs to be viewed with caution as the gene expression data was
to pathogenesis of PD (Maury, 2019). Thus, over the past decade, several normalized to a single, non-empirically validated reference gene, a
studies have investigated the association between polymorphisms in the practice which may cause misleading interpretation (Bustin et al., 2009;
clock genes and the risk of PD and its symptoms (Table 1). The earliest Tan, 2019; Tan et al., 2017). On the other hand, the functional impact of
study in this area of research was conducted by Hua et al. (Hua et al., the PER2 rs2304672 polymorphism is less well-understood, although it
2012) who investigated the association of CRY1 rs2287161 and CRY2 has been commonly found to be associated with a number of phenotypes
rs10838524 polymorphisms with depression symptoms in PD. The (Froy and Garaulet, 2018; Yegin et al., 2021). In the aforementioned
rs2287161 polymorphism is located 3’ downstream of the poly study by Lou et al. (2017), it was observed that the variant allele carriers
adenylation site of CRY1 and has been predicted to affect the binding of the CLOCK rs1801260 polymorphism showed almost a 2-fold risk of
and regulatory function of the RFX5 transcription factor (Gabriel and developing PD compared to individuals who did not carry the allele,
Zierath, 2019). Similarly, the intronic rs10838524 polymorphism of whereas significant association was not observed for the PER2 poly
CRY2 may hinder the binding of the CTCF transcription factor and may morphism. Further to this observation, the same group of researchers
therefore influence its transcription (Kovanen et al., 2017). In fact, examined the association between the CLOCK rs1801260 polymorphism
mathematical modeling suggest that the rs10838524 polymorphism can and various symptoms in PD in the same cases (Lou et al., 2018). They
cause an increased transcription rate of CRY2 (Liberman et al., 2018), did not find any significant association between the polymorphism and
although a study on breast tissues did not find a significant difference in dyskinesia, depression, or orthostatic hypotension. However, the variant
the expression levels of the gene among the different genotypes of the allele carriers of the polymorphism were observed to be more suscep
polymorphism (Lesicka et al., 2019). In the genetic association study tible to motor fluctuation and sleep disorder compared to non-variant
conducted by Hua et al. (2012) on 408 individuals with PD, it was found allele carriers.
that the homozygous CC genotype of the CRY1 rs2287161 poly
morphism was significantly associated with a higher score of Hamilton
7
7. Mitochondria dynamics and other pathways affecting Interestingly, PD has also been shown to be linked to human bio
circadian rhythmicity energetics. An example of this is the paradoxical kinesia (PK), where an
idiopathic PD patient may suddenly present excellent motor responses in
Although PD cases are often characterized as sporadic with unclear emotional or physical stress, due probably to noradrenergic augmenta
etiology, approximately 10% of the patients have well-defined genetic tion, compensatory activation of cerebellar circuitry, or activation of the
causes (as described above) and/or exhibit mitochondrial abnormalities basal ganglia reserves (Bonanni et al., 2010; de la Fuente-Fernández
(Alexiou et al., 2019, 2018b; Chen et al., 2019; Park et al., 2018). et al., 2002; Goerendt, 2004; Schlesinger et al., 2007). Latest studies
Mitochondria are a dynamic population of non-autonomous organelles have also revealed the correlation of mitochondrial bioenergetics in cell
that interact with each other. Neurons are reliant on mitochondrial metabolism to circadian rhythmicity (Aguilar-López et al., 2020; Puig
dynamics. Mitochondria are also actively recruited to subcellular sites et al., 2018), thus implicating clock genes in the regulation of glucose,
such as the axonal and dendritic neuron processes, where they are lipid homeostasis, and mitochondrial oxidative metabolism (de Goede
involved in critical cellular functions (Alexiou et al., 2018a; Rangaraju et al., 2018). Indeed, in vitro models have presented the relationship
et al., 2019; Seager et al., 2020). Thus, disruptions in mitochondrial between clock gene expression and the mitochondrial oxidative phos
dynamics are highly correlated to neurodegeneration (Johnson et al., phorylation (Silva Ramos et al., 2016). Using synchronized cells, re
2021; Tapias, 2019). searchers have achieved an autonomous ultradian mitochondrial
High mitochondrial fusion and fission rates are independent events respiratory activity abrogated by silencing the BMAL1. In contrast,
in a wild-type cell, which constantly change individual mitochondria’s pharmacological inhibition of the mitochondrial oxidative phosphory
identity (Fig. 3). Mitochondria mix their contents through fusion, lation system resulted in dramatic deregulation of the rhythmic
enabling protein complementation, mtDNA repair, equal distribution of clock-gene expression (Scrima et al., 2016). New pieces of evidence have
metabolites, and autophagy of isolated damaged mitochondrial seg also identified the connection between circadian timekeeping disruption
ments (Twig et al., 2008). On the other hand, fission facilitates equal and abnormalities in mitochondrial dynamics in several neurodegener
segregation of mitochondria into daughter cells during cell division and ative diseases like AD, PD, and HD (Aguilar-López et al., 2020; Oli
enhances mitochondrial distribution along cytoskeletal tracks. Mito va-Ramírez et al., 2014; Videnovic et al., 2014a). For example, Bmal1
chondrial fission is regulated by dynamin-related protein (Drp-1), while has been shown to affect mitochondrial fusion in the heart via mecha
fusion is regulated by optic atrophy 1 (Opa1) and mitofusins (Mfn) 1 and nisms unrelated to Drp-1, Opa1 and Mfn1/2 (Jacobi et al., 2015; Koh
2 (Frezza et al., 2007). Disruptions in both fusion and fission have been saka et al., 2014). In addition, the peroxisome proliferator-activated
shown to affect mitochondrial movement, thus affecting their functions. receptor gamma coactivator 1 alpha (PGC-1α), a key inducer of mito
Therefore, abnormalities in fission and fusion have been thought to chondrial biogenesis, is known to be expressed in a rhythmic manner
contribute to PD pathogenesis (Mani et al., 2021). In addition, failure in and stimulates the transcription of BMAL1 and CLOCK via interactions
fission and fusion can impede the mitophagy process, which is mediated with RORa and RORb proteins (de Goede et al., 2018; Liu et al., 2007).
mainly through the Pink1/Parkin pathway (de Goede et al., 2018). Several other studies also found that PARKIN mutations are strongly
Parkin targets mitochondria with low membrane potential, which are correlated with the circadian machinery of the mitochondrial dynamics
then destroyed through the autophagosome. Recent studies revealed (Breen et al., 2014b; Jacobi et al., 2017; Pacelli et al., 2019). These
that Pink1 and Parkin also play a role in promoting mitochondrial fission findings provide a clear indication of the involvement of clock genes in
or inhibiting fusion (Gao et al., 2021; Ma et al., 2018; Peng et al., 2018). mitochondrial dynamics in neurodegenerative diseases like PD.
For this reason, aberrations in PINK and PARKIN genes which encode the The role of clock genes in PD pathogenesis is not only limited to
two proteins have been seen in a number of neurodegenerative diseases mitochondria dynamics. The molecular circadian clock also regulates
like the Alzheimer’s disease (AD), Huntington’s disease (HD), as well as antioxidative defense, which plays a major role in initiating a cascade of
PD (Quinn et al., 2020). biochemical processes that cause dopaminergic cell death. For this
Fig. 3. Circadian interactions and mitochondrial dynamics. Clock-Bmal1 stimulates mitochondrial biogenesis by regulating mitochondrial fission and fusion.
(Adapted from de Goede et al., 2018, an Open Access Article, (CC BY 4.0)).
8
reason, mitochondrial complex I inhibitors, a well-known source of Videnovic et al. illustrated that both the melatonin rhythm and the
oxidative stress, show cytotoxicity to dopaminergic neurons can cause area-under-the-curve (AUC) in 24 h for circulating melatonin levels
neural apoptosis (Blesa and Przedborski, 2014; Greenamyre et al., were dramatically lower in PD patients compared to controls (Videnovic
2010). Besides, alterations to the antioxidative SIRT1 gene have been et al., 2014b).
known to affect the circadian rhythm and the expression of Since both melatonin and clock genes play a substantial role in PD,
clock-controlled genes by deacetylating Bmal1 and Per2 proteins, which several studies have investigated the targeting of clock genes for PD
again provided an evidence of the importance of clock genes in regu treatment using melatonin. For example, Dowling et al. conducted a
lating oxidative stress during PD pathogenesis (Dong et al., 2016; Wang comparative study to assess the effect of melatonin treatment on
et al., 2018a). Thus, circadian disruptions may result in increased nocturnal sleep of 40 PD patients with sleep disorders, where the pa
oxidative stress, which accelerate neurodegeneration in PD (Videnovic tients took either 5 mg or 50 mg melatonin, or placebo, during different
et al., 2014a). Targeting the redox homeostasis process could therefore study periods (Dowling et al., 2005). The results showed that there was a
be a potential treatment procedure for PD (Wang et al., 2018a). slight improvement in night sleep when the patients received 50 mg
Clock genes are also implicated in the regulation of autophagy, melatonin, when compared to the placebo treatment period, although
which plays a major function in mediating the protein and cellular the improvement lasted for only around 10 min (Dowling et al., 2005).
turnover (Hou et al., 2020). Dysfunction in autophagy can cause the However, during the 5 mg melatonin treatment period, the patients
accumulation of α-synuclein and the degeneration of dopaminergic showed a substantial amelioration in subjective sleep disturbance and
neurons, which contribute to PD. It is for this reason that several daytime sleepiness (Dowling et al., 2005). Interestingly, in a later
autophagy-related genes, such as LRRK2, are commonly mutated in PD double-blind, randomized, placebo-controlled study conducted on 18
(Kim et al., 2019). Additionally, since autophagy also regulate immune PD patients, a robust enhancement in subjective sleep quality was
cell homeostasis and survival, impairment in the autophagy process observed in patients administered 3 mg/day melatonin for 4 weeks,
promotes neutrophilic infiltration, activates inflammasome and facili although the polysomnography results showed no change (Medeiros
tates significant proinflammatory cytokine alterations (Hu et al., 2021; et al., 2007). Recently in 2020, Delgado-Lara et al. conducted a ran
Qian et al., 2017). These processes lead to neuroinflammation, which is domized controlled trial involving 26 PD patients to investigate the in
widely known to cause neurodegeneration by mediating the progressive fluence of melatonin administration on PER1 and BMAL1 genes
loss of nigral dopaminergic neurons. Besides, inflammation also con expression. When 25 mg melatonin was administrated for a period of 3
tributes to oxidative stress, and is in fact, exacerbated by oxidative months at noon and before sleep, increased BMAL1 level was docu
stress; thus forming a vicious cycle with each other during the patho mented in the patients, especially in the morning, but significant
genesis of PD (Pajares et al., 2020; Racanelli et al., 2018). Autophagy is changes were not observed in the level of PER1 (Delgado-Lara et al.,
not only involved in neurodegenerative diseases, but is also highly 2020). This suggests that melatonin improves PD symptoms by regu
correlated with cognitive loss (Crino, 2016) and circadian rhythm lating BMAL1 expression. Despite this, treatment with melatonin did not
dysfunction (Vaiserman et al., 2016). In addition, alterations in affect or delay the disease progress, insomnia, or daytime sleepiness,
everyday life activities, such as sleep disturbances and the absence of although it was found to enhance the perception of sleep comfort
circadian clock proteins, may influence the autophagy process and result (Delgado-Lara et al., 2020). Besides, another study investigated the role
in cognitive decline (Maiese, 2017). Given the importance of autophagy of melatonin on clock genes by using male rotenone-induced PD (RIPD)
in PD, a recent study has demonstrated the potential of controlled Wistar rat models. The results showed that melatonin intervention
autophagy induction as an efficient clinical PD therapy procedure restored the phase of the rPer1 daily rhythm in the RIPD models.
(Ajoolabady et al., 2021). Targeting the autophagy pathway in PD Interestingly, when melatonin and rotenone were administered to the
therapy will thus be an interesting avenue for research in the near RIPD models for 48 days, neuroprotective effects were observed in the
future. dark phase (Mattam and Jagota, 2015).
Cortisol is a stress hormone which is the end product of the
8. Hormonal destabilization in PD involved clock genes hypothalamic-pituitary-adrenal (HPA) axis under strong circadian con
trol. It is involved in depression, sleep disorders, and anxiety. The
PD patients often show altered endocrine hormonal secretion. The cortisol secretory rhythms serve as an indicator of circadian function,
SCN, which generates the circadian rhythms, is known to control the that is altered in PD patients as well (Mlili et al., 2021; Nandam et al.,
rhythmic synthesis and secretion of such hormones as melatonin and 2020). Cortisol level in the serum was found to be significantly elevated
cortisol (Mlili et al., 2021). Melatonin is a natural hormone that is in PD patients, as demonstrated by Breen et al. (Breen et al., 2014a,
formed primarily in the pineal gland during the dark period. Its secretion 2014b). Moreover, half of the PD patients exhibited arrhythmic cortisol
normally starts at dusk and ends at dawn, and it has a substantial role in levels with no phase shifting, either to an earlier phase or to a delayed
the sleep-wake cycle regulation and control (Kenneth et al., 2013). Since phase (Breen et al., 2014a, 2014b). Likewise, Hartmann et al. showed
sleep disorders are one of the most common non-motor symptoms in PD that the total plasma cortisol level was enhanced in PD patients
patients, serum level of melatonin has been investigated in PD patients compared to age-matched volunteers (Hartmann et al., 1997). Similarly,
for a long time. In 1991, a study by Fertl et al. showed that the level of the salivary cortisol level was found to be higher in PD patients without
serum melatonin was similar between PD patients and non-PD controls impulsive compulsive behaviors compared to the non-PD controls
(Fertl et al., 1991). However, when comparison was made between de (Djamshidian et al., 2011). It has also been observed that cortisol is
novo PD patients and those treated with L-Dopa, it was found that the involved in stress regulation, as serum cortisol levels are intimately
phase was advanced in the latter group (Fertl et al., 1993). Dopami linked to various neuropsychiatric symptoms. For example, a higher
nergic treatment enhanced the melatonin secretion cause sleep delay level of cortisol has been associated with longer sleep latency and a
suggesting an uncoupling of circadian sleep regulation due to pharma lower sleep efficiency and duration in PD patients (Breen et al., 2014a,
cological alteration of the melatonin level (Bolitho et al., 2014). In 2014b). Another study demonstrated that cortisol levels were negatively
another study examining the impact of dopaminergic treatment in PD linked to anxiety level (Růžička et al., 2015). In addition, pattern of the
patients on circadian melatonin secretion patterns, it was noted that the daily cortisol secretion has been found to be correlated with depression
level of melatonin was decreased at night, while increased in the day scores after 3 and 6 months (Seifried et al., 2013). These observations
time (Bordet et al., 2003). On the other hand, a study done by Breen clearly demonstrate the important roles of cortisol, which is regulated by
et al. found that the melatonin level was decreased in PD patients who circadian clock, in PD and its symptoms. Besides, in MPTP-treated dog
were in the early disease stage and suffering from sleep disorders (Breen models of PD, an increase in the plasma cortisol level was observed,
et al., 2014a, 2014b). In agreement with Breen et al., another study by indicating that MPTP has an impact on the activity of the dog’s
9
hypothalamic neurons (Mizobuchi et al., 1993). Animal studies have studies could there contribute to misleading result interpretations (Tan,
also demonstrated a link between elevated cortisol level with dopami 2019). In addition, none of the studies profiled the expression of all six
nergic cell loss and motor handicap, which could explain why increased (or more) clock genes simultaneously, thus the impact of gene-gene
cortisol level is commonly found in PD patients (Djamshidian et al., interactions is not well-understood. Likewise, possible
2011). A few attempts have also been made to examine the level of gene-environment interactions are not known. Majority of epigenetics
cortisol following PD treatments. For example, in a randomized studies have also focused only on DNA methylation, even though the
controlled pilot study investigating the diurnal as well as the total sali involvements of other epigenetic mechanisms, such as histone acetyla
vary cortisol levels during short- and long-term points of tactile massage tion and microRNAs, are becoming more apparent (Jakubowski and
(TM), it was revealed that the salivary cortisol level was decreased after Labrie, 2017). More research is needed to provide further insights into
the intervention, while the diurnal cortisol level remained constant the roles of clock genes in PD.
(Törnhage et al., 2013). A more recent study on 6-OHDA-treated rats Apart from that, in the current era of genomics and precision med
found an increased cortical secretion at 06:00 following L-Dopa icine, it is imperative that genome-wide (and epigenome-wide) associ
administration (Li et al., 2017c). Interestingly, L-Dopa treatment caused ation studies are conducted on a large scale to shed some light on the
a reduction in the expression level and delayed the phase of clock genes, genetic variants associated with PD. Additional in vitro and in vivo
specifically BMAL1 at the 4:00 ZT and 16:00 ZT time points in the SCN functional assays should also be performed to clarify the mechanisms by
and at 10:00 ZT in the striatum (where the PER2 expression was delayed which the clock genes contribute to the pathogenesis of PD (Pierce et al.,
to 16:00 ZT), while no changes were observed in the expression of any of 2020). Of particular interest are the studies of how the clock genes
the clock genes in the liver (Li et al., 2017c). It is unknown, however, regulate mitochondrial dynamics and how abnormalities in these dy
whether the gene expression and phase changes were due to the direct namics drive PD, since current evidence has provided a solid foundation
effect of L-Dopa, or the dopamine that is converted from the former. in this field for future research. It would also be interesting to investigate
Nonetheless, these findings suggest that the link between clock genes the changes in the levels of hormones other than cortisol and melatonin
and cortical secretion occur in a tissue-specific manner. Besides, L-Dopa in response to clock gene regulation.
is also known to have a direct effect on clock gene regulation in PD rat In conclusion, it is now clear that clock genes could contribute to PD
model (Korshunov et al., 2017). Notably, dopamine and its receptors via a number of mechanisms. However, more research will be needed to
could have both direct and indirect effect on clock genes in the central provide a complete picture of the roles of clock genes in the pathogenesis
nervous system. Additionally, dopamine can possess clock gene-like of PD. These additional research data will be necessary for knowledge in
activities, like those in the retina, midbrain, and hypothalamus. In this area of study to be deemed sufficiently reliable for future clinical
such areas, dopamine and clock genes can regulate each other (Kor applications.
shunov et al., 2017). Considering these, it has now become clear that the
clock genes play an undeniably important role in the pathogenesis and CRediT authorship contribution statement
recovery of PD.
Anastasiia Dmytrivna Shkodina: Conceptualization, Writing –
9. Conclusions and future perspectives original draft, Visualization. Shing Cheng Tan: Writing – original draft,
Writing – review & editing, Supervision, Project administration.
Circadian rhythm is regulated by six major clock genes, namely Mohammad Mehedi Hasan: Writing – original draft. Mai Abdelga
CLOCK, BMAL1, PER1, PER2, CRY1 and CRY2. The loss of circadian wad: Writing – original draft. Hitesh Chopra: Writing – original draft.
rhythm, presumably due to disruptions in the levels and functions of Muhammad Bilal: Writing – original draft. Dmytro Ivanovych Boiko:
clock genes, is a common event in the development of PD. Thus, Visualization. Kateryna Anatoliivna Tarianyk: Writing – original
although the role of clock genes in the pathogenesis of PD has not been draft. Athanasios Alexiou: Writing – original draft.
extensively studied, current evidence points to the indication that they
may have a significant impact on the development and progression of Conflict of interest
the disease. This assertion is corroborated by the observation in human
subjects that the expression of clock genes is dysregulated in PD patients. The authors declare that they have no conflict of interest.
Epigenetics, along with genetic polymorphisms, have been pinpointed
as some of the possible mechanisms through which dysregulated clock Acknowledgements
gene expression is achieved. Additionally, a few polymorphisms in the
clock genes have been found to be associated with risk and/or symptoms Research in the authors’ laboratories is supported by the Research
of PD. It has also been postulated that clock genes contribute to the University Grant of Universiti Kebangsaan Malaysia (No. GUP-2020-
pathogenesis of PD by disrupting the mitochondrial dynamics. Besides, 076), the Fundamental Research Grant Scheme of the Malaysian Min
abnormalities in the circadian rhythm of hormone secretion have also istry of Higher Education (No. FRGS/1/2019/SKK08/UKM/02/9), the
been noted, which can be considered as a marker of circadian regulation Ministry of Health of Ukraine (research project No. 0120U101166), and
dysfunction. These findings provide a strong support for the potential the Poltava State Medical University (research project No.
role of clock genes in PD pathogenesis. 0119U102848, 0121U108235).
Despite this, several pieces of information are still missing as there
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Ageing Research Reviews 74 (2022) 101554

Contents lists available at ScienceDirect

Ageing Research Reviews

Roles of clock genes in the pathogenesis of Parkinson’s disease

1. Introduction disturbances, excessive secretion of saliva, and some neuropsychiatric

several studies have established a link between photoentrainment and

phenomenon at least to the motor phenotypes of the disease, which Table 1

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