REVIEW ARTICLE

CELLULAR NEUROSCIENCE
published: 27 February 2015
doi: 10.3389/fncel.2015.00058

Epigenetic mechanisms in neurological and

neurodegenerative diseases
Jorge Landgrave-Gómez , Octavio Mercado-Gómez and Rosalinda Guevara-Guzmán *
Facultad de Medicina, Departamento de Fisiología, Universidad Nacional Autónoma de México, México, D.F., México

Edited by: The role of epigenetic mechanisms in the function and homeostasis of the central nervous
Victoria Campos-Peña, Instituto
system (CNS) and its regulation in diseases is one of the most interesting processes of
Nacional De Neurologia Y
Neurocirugia, Mexico contemporary neuroscience. In the last decade, a growing body of literature suggests that
Reviewed by: long-term changes in gene transcription associated with CNS’s regulation and neurological
Alexander K. Murashov, East disorders are mediated via modulation of chromatin structure. “Epigenetics”, introduced
Carolina University, USA for the first time by Waddington in the early 1940s, has been traditionally referred to
Jose F. Maya-Vetencourt, Italian
a variety of mechanisms that allow heritable changes in gene expression even in the
Institute of Technology, Italy
absence of DNA mutation. However, new definitions acknowledge that many of these
*Correspondence:
Rosalinda Guevara-Guzmán, mechanisms used to perpetuate epigenetic traits in dividing cells are used by neurons
Facultad de Medicina, to control a variety of functions dependent on gene expression. Indeed, in the recent
Departamento de Fisiología, years these mechanisms have shown their importance in the maintenance of a healthy
Universidad Nacional Autónoma de
CNS. Moreover, environmental inputs that have shown effects in CNS diseases, such
México, Ave. Universidad # 3000
Col. UNAM Delegación Coyoacán, as nutrition, that can modulate the concentration of a variety of metabolites such as
Apartado Postal No. 70250, 04510 acetyl-coenzyme A (acetyl-coA), nicotinamide adenine dinucleotide (NAD+ ) and beta
México, D.F., México hydroxybutyrate (β-HB), regulates some of these epigenetic modifications, linking in
e-mail: [email protected]
a precise way environment with gene expression. This manuscript will portray what
is currently understood about the role of epigenetic mechanisms in the function and
homeostasis of the CNS and their participation in a variety of neurological disorders. We
will discuss how the machinery that controls these modifications plays an important role
in processes involved in neurological disorders such as neurogenesis and cell growth.
Moreover, we will discuss how environmental inputs modulate these modifications
producing metabolic and physiological alterations that could exert beneficial effects on
neurological diseases. Finally, we will highlight possible future directions in the field of
epigenetics and neurological disorders.

Keywords: epigenetics, neurodegeneration, DNA methylation, postranslational modification, Parkinson disease,

epilepsy

EPIGENETICS into being” (Waddington, 1968). In the original sense of this

The term epigenetics is derived from the theoretical and definition, epigenetics is referred to all molecular pathways
experimental work of Conrad Waddington. He coined the modulating the expression of a genotype into a particular
term to describe a conceptual solution to a phenomenon that phenotype.
arises as a fundamental consideration of developmental biology However, and with the fast expansion in this field, epigenetics
(Waddington, 1942). All of the different cells in the body of has been redefined and accepted today as “the study of changes
one individual have exactly the same genome, that is, exactly in gene function that are mitotically and/or meiotically heritable
the same DNA nucleotide sequence, with only a few exceptions and that does not entail a change in DNA sequence.” In this
in the reproductive, immune and nervous systems. Thus, in way, recent advances have evolved our understanding of classical
the vast majority of instances, one’s liver cells have exactly epigenetic mechanisms and the broader landscape of molecular
the same DNA as neurons. However, those two types of cells interactions and cellular functions that are inextricably linked
are clearly vastly different in terms of the gene products that to these processes. The current view of epigenetics includes the
they produce. Some level of mechanism must exist, Waddington dynamic nature of DNA methylation, active mechanisms for DNA
reasoned, that is “above” the levels of genes encoded by the demethylation, differential functions of 5-methylcytosine and
DNA sequence, which controls the DNA readout. For this its oxidized derivatives, the intricate regulatory logic of histone
reason, he defined the term epigenetics in the early 1940s as post-translational modifications, the incorporation of histone
“the branch of biology which studies the causal interactions variants into chromatin, nucleosome occupancy and dynamics.
between genes and their products which bring the phenotype Nevertheless, of all these modifications, the mechanisms better

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Landgrave-Gómez et al. Epigenetic mechanisms in neurological and neurodegenerative diseases

described in literature generally comprise histone variants, Belkacemi et al., 2012; Kroeger et al., 2012; Lee et al., 2012; Varady
posttranslational modifications of amino acids on the amino- et al., 2013; Colman et al., 2014).
terminal tail of histones, and covalent modifications of DNA Consistently, some reports have shown that aging it’s a
bases. process that may be altered through some diets, such as calorie
In this chapter, we will discuss some of these epigenetic restriction (Colman et al., 2014). The precise mechanisms
modifications and how these modifications are associated with of how environment mediates epigenetic modifications are
neurologic homeostasis and diseases. not clearly understood, however in this manuscript we will
portray some studies that aim to epitomize the relationship
LINKING THE ENVIRONMENT, NUTRITION AND EPIGENETIC between environment, metabolism, epigenetics and neuro
MODIFICATIONS -logical/neurodegenerative diseases.
Although many aspects of nutrition and different kinds of
lifestyles influence metabolic status and disease trajectory EPIGENETIC MODIFICATIONS
throughout our life, emerging findings suggest that changing Within cell nucleus, the fundamental units of chromatin are
our metabolism with exercise or different dietary regimens such named nucleosomes. Each nucleosome is formed by 147 DNA
as ketogenic diets, low-carbohydrate diets, intermittent fasting base pairs wrapped tightly around an octamer of histone proteins,
or physical exercise can alter the concentration of a variety of which is assembled by two copies of each of the four core histones
metabolites, some of them capable of modulating the activity of (H2A, H2B, H3 and H4). The linker histone H1 binds to the
proteins that elicit epigenetic modifications (Figure 1; Shimazu DNA between the nucleosomal core particles, and their function
et al., 2013; Shyh-Chang et al., 2013). is to stabilize higher order chromatin structures. Moreover,
These epigenetic modifications seem to regulate important each histone protein consists of a central globular domain
networks of genes mediating physiological processes associated and N-terminal tail that contains multiple sites for potential
with the beneficial effect of these diets, providing a rationale modifications (Wang et al., 2013).
and simple way to prevent or even treat these diseases. Some In this regard, a variety of different modifications on
reports have shown the efficacy of exercise and diet in cancer; amino acid residues of histones have been described. Histone
cardiovascular disease, diabetes, obesity, rheumatoid arthritis posttranslational modifications include acetylation, methylation,
and even in some neurological/neurodegenerative diseases such phosphorylation, ubiquitination and sumoylation (Table 1;
as Alzheimer and epilepsy (Müller et al., 2001; Ahmet et al., 2005; Sassone-Corsi, 2013).
The principal residues that are substrates of these
modifications are lysine, arginine, serine and threonine amino
acids (Rothbart and Strahl, 2014). These modifications have
been associated to repression or activation of gene transcription
depending on the site of the modification, strongly suggesting the
existence of a histone code. This hypothesis proposes that specific
modifications of histones induce to the interaction with proteins
associated with the chromatin, producing a differential regulatory
response of gene expression (Strahl and Allis, 2000; Table 1 and
Figure 2). These modifications are dynamic in the way that they
are actively added and removed by histone-modifying enzymes
in a site-specific manner, which is essential for coordinated
transcriptional control.

Table 1 | Histone posttranslational modifications and their role on

transcription.

Modification Role in transcription Modification site

Acetylation Activation H3(K9, K14, K18, K56).

H4(K5, K8, K12, K16).
H2B(K6, K7, K16, K17)
(Strahl and Allis, 2000).
Methylation Activation H3(K4me2, K4me3,
FIGURE 1 | Linking lifestyle with genome expression. DNA and the
proteins that provides chromatin structure are targets of multiple
K36me3, K79me2)
modifications. In this way, changes in our lifestyle (diets or physical activity) (Strahl and Allis, 2000)
via the modulation of the metabolism alters the concentration ratio of Methylation Repression H3(K9me3, K27me3)
different metabolites. The availability and cellular compartamentalization of and H4(K20me3)
these metabolites alters the activity of proteins capable to elicit epigenetic (Balazs, 2014).
modifications, contributing to the specificity of the genome expression. Phosphorylation Activation H3(S10)
NAD, nicotine adenine dinucleotide (Modified from Sassone-Corsi, 2013). (Strahl and Allis, 2000)

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HISTONE METHYLATION
Histone methylation is currently associated with multiple
processes such as transcriptional activation and repression,
depending on the modified amino acid residue (Figures 2C,D).
This modification occurs mainly on arginine and lysine residues.
Additionally, these residues could be methylated multiple times
giving different signals depending on how many times the
residue is methylated, making its analysis difficult. In this
regard, current literature has shown that lysine residues can be
methylated even three times; meanwhile, arginine residues can
only be methylated twice (Strahl and Allis, 2000). Furthermore,
there have been some studies associating some processes with
these types of modifications for example H3K4, H3K36 and
H3K79 are associated with chromatin aperture. Nevertheless,
the methylation of these residues has been also associated
with other specific functions. On the other hand, H3K4
trimethylation has been associated with promoter regions. The
monomethylathion of this same residue recruits regulatory
elements that potentiate the promoter activity; such elements are
known as enhancers. Dimethylation of H3K36 has been related
to RNA POL II elongation during transcription (Li et al., 2007).
Also, the dimethylation of H3K79 is particular of promoter
regions stimulating a permissive chromatin for local transcription
(Jacinto et al., 2009). Conversely, the modifications associated
with transcriptional repression are performed on H3K9 and
H3K27 residues (Baylin and Jones, 2011).

DNA METHYLATION
In mammalians, DNA methylation is the covalent union of
methyl groups of cytosines that are found mainly in the context
of dinucleotide 50 -CpG-30 (Figure 3A; Klose and Bird, 2006).
The addition of methyl groups protrudes above the major
groove and when DNA is symmetrically methylated, the methyl
groups promote a conformational change of DNA structure.
The main consequence of methyl modification is that a variety
FIGURE 2 | Histone posttranslational modifications. (A) Schemes
of transcription factors cannot recognize the DNA and thus
representing the interaction of the N-terminal dominium of acetylated induce repressional transcription (Prokhortchouk and Defossez,
histones with the DNA strand (A) and the interaction of a non-acetylated 2008).
histone with the DNA strand (B). It can be noticed that acetylated histones DNA methylation generates patterns that are established
have a minor interaction with DNA strand compared with that of
during embryonic development and such patterns are maintained
non-acetylated histones whose positive charges are attracted to negative
charges of DNA. (C) On the other hand different specific marks of
by a mechanism when DNA replicates (Figure 3). Interestingly,
methylation of histone 3 are associated with both transcriptional activation these patterns change over time, principally due to environmental
(C) and repression (D). Also a specific mark of phosphorylation on the (S10) factors (i.e., nutrition, metabolites, exercise, chemical agents)
amino acid of histone 3 has been associated with transcriptional activation (Fraga et al., 2005). The mechanism of DNA methylation
(E) so the lack of this mark may be associated with transcriptional
is carried out by a set of proteins named DNA methyl-
repression (F).
transferases (DNMTs). There are two groups of these proteins;
(1) one for de novo methylation; and (2), one for methylation
HISTONE ACETYLATION maintenance. Both enzymes differ depending on the DNA
The acetylation of histones is a modification associated generally substrate: for example, maintenance of DNA methylation is
to transcriptional activity that indicates access of the transcription accomplished by DNA methyl transferase 1 (DNMT1). These
machinery to the genes and thus active mechanisms (Strahl proteins add methyl groups to pre-existing methyl patterns on
and Allis, 2000; Balazs, 2014). This effect could be explained a new strand of DNA during replication (Figure 3B; Jeltsch,
by the chemistry of this modification in which an acetyl group 2006). On the other hand, de novo DNA methylation are
(−COCH3) is incorporated to an amino terminal residue and carried out by DNMT3a and DNMT3b. Such proteins are
thus, the positive charge of histones is reduced, inducing a minor responsible for the addition of new methyl groups to cytosines
interaction with DNA resulting in a decrease of the chromatin that have not been methylated previously (Goll and Bestor,
compaction (Figures 2A,B; Shahbazian and Grunstein, 2007). 2005).

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Landgrave-Gómez et al. Epigenetic mechanisms in neurological and neurodegenerative diseases

FIGURE 3 | DNA methylation. Scheme showing the addition of a methyl group on the 5 carbon of cytosine in the context of 50 -CpG-30 dinucleotide (A). The
maintenance of DNA methylation is accomplished by DNA methyl-transferases (DNMT1) when DNA replication occurs (B).

HISTONE VARIANTS roles in the development, maintenance, and plasticity of the

Histone variants such as H2A and H3.3 have been known CNS (Chao et al., 2006) have been demonstrated to play an
since several decades ago and recently, a lot of evidence has important role on different psychiatric disorders associated with
been accumulated about their role in their participation on the early-life adversity, including depression; schizophrenia, bipolar
differential structure of chromatin (Henikoff et al., 2004). Among disorder and autism. Even when the underlying mechanisms of
them, H2A.Z has been located on DNA regions associated with the alterations over the expression of BDNF are unknown in
transcriptional activation, mainly, on promoter regions. This these conditions, epigenetic modifications seem as a plausible
variant is important because it induces a less stable structure candidate, as early-life exposures, chronic emotional stimuli, or
of chromatin compared with that of the canonical histone H2 even emotional behavior, disrupts epigenetic programming in the
(Draker and Cheung, 2009). Another histone variant associated brain with lasting consequences for gene expression and behavior
with promoter regions is H3.3. This variant as well as H2A.Z, is (Renthal et al., 2007; LaPlant et al., 2010; Kundakovic et al.,
mainly found on promoter regions suggesting that their structure 2014).
promotes the formation of a more permissive chromatin (Jin However, epigenetics is such a new field of science that in most
et al., 2009). of the cases, its impact has not been fully demonstrated. Even
though, it is now clear that there is a dynamic interplay between
NEUROEPIGENETICS AND THEIR ROLE IN NEURONAL genes and experience, a clearly delineated and biochemically
FUNCTION driven mechanistic interface between genes and environment, this
Over the last two decades, the field of epigenetics, particularly interface is epigenetics (Sweatt, 2013).
the emerging field of neuroepigenetics, has begun to have a
great impact in different areas such as the study of the CNS ALZHEIMER’S DISEASE AND EPIGENETICS
development, learned behavior, neurotoxicology, cognition, Alzheimer’s disease (AD) is an age-related and slowly
addiction and lately neurological and neurodegenerative neurodegenerative disorder of the brain and the most common
pathology (Sweatt, 2013). In this regard, epigenetics has form of dementia in the elderly (Sezgin and Dincer, 2014). The
undergone an exponential expansion. A quick search of the disease is clinically characterized by progressive memory loss and
PubMed database reveals that about 98% of all the research cognitive impairment. Moreover, the histopathological features
work on epigenetics was published within the last 15 years of AD are senile plaques composed of amyloid beta (Aβ) fibrils
(Sweatt, 2013). Thanks to these studies, nowadays we know and neurofibrillary tangles composed of microtubule-associated
that either maternal behavior, environmental toxins, nutrition, protein tau, combined with massive cholinergic neuronal loss,
physociological or physical stress, learning, drug exposure mainly in the hippocampus and association regions of neocortex
or psychotrauma, leads to active regulation of the chemical (Hardy, 2006; Ballatore et al., 2007). This disease currently affects
and three-dimensional structure of DNA and thus, regulates approximately 2% of the population in industrialized countries
epigenetics modifications in the CNS linking environmental and its incidence will increase dramatically over the time (Sezgin
stimuli and gene expression regulation (Tsankova et al., 2007; and Dincer, 2014).
Borrelli et al., 2008; Renthal and Nestler, 2008; Champagne and AD is a multifactorial disease involving; genetic, metabolic,
Curley, 2009; Day and Sweatt, 2010; Dulac, 2010). nutritional, environmental and social factors that are associated
These epigenenomic changes allow perpetual alterations in with onset and progression of the pathology. For this reason, and
gene readout in cells in the CNS affecting neuronal function considering that the main risk factor of this disorder is aging, it is
and physiology. For example, a central regulator of homeostasis reasonable to think that life history such hypertension, diabetes,
in the brain, the brain-derived neurotrophic factor (BDNF), a inflammation, obesity or head injury are closely related with
member of the neurotrophin family of proteins that plays crucial AD (Marques et al., 2011). However, how these factors induce

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epigenetic changes that mediate the network genes involved in this Table 2 | Epigenetic modifications implicated in Alzheimer’s disease.
disease is a question that remains to be answered.
Observation Sample
At present, studies of epigenetic changes in AD are starting to
emerge. As we mentioned before, aging is the most important risk APP promoter hypomethylation in Human brains.
factor for AD an epigenetic changes have been observed in aging Alzheimer’s disease patients (Miller, 2003).
tissues. Recently, it has been observed that environmental factors Hypomethylation of promoters of ribosomal Human lymphocytes.
genes with aging (Decottignies and d’Adda
even transient ones in early life can induce AD-like pathogenesis
di Fagagna, 2011).
in association with aging (Wu et al., 2008a). Furthermore, a Decrements in DNA methylation Human prefrontal cortex.
difference in DNA methylation patterns typical of brain region (Al-Mahdawi et al., 2014).
and aging has been identified in this context (Balazs, 2014). In Differences in DNA methylation in a twin Human temporal neocortex.
this regard, a recent study by Hernandez et al. examined the pair discordant for Alzheimer’s disease
DNA methylation patterns in >27,000 CpG sites from donors (Al-Mahdawi et al., 2014).
APP promoter methylation Intact and gonadectomized
ranging in age 4 months to 102 years and a strong relationship
influenced by sex steroids and aging mice brains.
was found between DNA methylation and aging. Moreover, in the (Maloney et al., 2012).
temporal and frontal cortices pons and cerebellum regions, more PSEN1 is regulated by DNA methylation in Non-human primate cortical
than 1,000 associations were found between DNA methylation response to metabolic stimuli areas of mice brains.
at CpG sites and age and some associations were significant in (Zetzsche et al., 2010).
all four regions. Interestingly, the majority of the association sites
were in CpG islands and the pattern was similar in the frontal
cortex, temporal cortex and pons, but different in cerebellum. functions and biological processes, including hypermethylation
These results suggest that and age-dependent increase in DNA of genes involved in transcription and DNA replication, while
methylation may be important for maintaining gene expression membrane transporters were hypomethylated (Bakulski et al.,
with age (Hernandez et al., 2011). 2012).
As it has been reported in many studies, memory can be Also, some reports have focused on research DNA methylation
compromised during aging. Preclinical and basic studies have at the 50 promoter regions of candidate genes according to the
shown that epigenetic mechanisms are involved in formation basis of hypothesis concerning the molecular mechanisms of
and maintenance of memory (for reviews, see Levenson and AD as microtubule-associated protein tau, amyloid precursor
Sweatt, 2005; Zovkic et al., 2013; Jarome et al., 2014). For protein (APP) and preseniline-1 genes in the frontal cortex
example, inhibition of DNA methylation has deleterious effects and hippocampus of both control and AD cases at different
on neuronal plasticity together with histone modifications (Day Braak stages. Interestingly, there wasn’t any significant difference
and Sweatt, 2011; Zovkic et al., 2013). Moreover, it has been on CpG methylation between the control and AD samples
observed that associative learning was impaired in 16-month- (Barrachina and Ferrer, 2009). Other studies have reported
old mice compared with that of 3-month-old mice which was hypomethylation of APP in the promoter region of normal 70
associated with specific reduction in acetylation of H4K12 (Peleg year-old human brain (Tohgi et al., 1999). However, as mentioned
et al., 2010). above, no difference was found in methylation of selected regions
Until now, most of the studies have analyzed DNA of the APP gene in various stages of AD progression (Barrachina
methylation in the brain of AD patients (Balazs, 2014). and Ferrer, 2009). Also, it has been found that the change in
In this regard, a variety of studies suggest a genome-wide methylation status differed among transcription factor binding
decrease in DNA methylation present in aging and AD sites of tau promoter (Wang et al., 2013).
patients (Table 2; Mastroeni et al., 2011). Interestingly, the Additionally to DNA methylation, histone modifications have
folate/methionine metabolism is critically linked with DNA been studied in recent years. Francis et al. investigated histone
methylation mechanisms, consistently with this fact; studies show acetylation in mouse models of AD. In APP/presenilin1 double
that folate and S-adenosyl methionine are significantly decreased mutant transgenic mice, associative learning was impaired and
in AD (Bottiglieri et al., 1990; Morrison et al., 1996). All this this was linked to a marked reduction in H4K14 histone
data indicates that AD patients produce a hypomethylation acetylation (Francis et al., 2009). Furthermore, studies in vitro
across the DNA genome. Recently, Bakulski et al. provided a have shown that exposure of cortical and hippocampal cultures
semi-unbiased, quantitative, genome-wide localization of DNA to Aβ oligomers resulted in increased levels of acetylated H3K14
epigenetic differences in frontal cortex of control and AD cases. and a loss of dendritic spines, which was prevented by inhibition
These authors determined DNA methylation of 27, 587 CpG of histone acetyl transferase. Also, in young pre-plaque AD
sites spanning 14,475 genes. Interestingly, they found that in transgenic mice, these authors observed markedly increased
control samples, the methylation state is markedly affected by levels of H3K14 and H3K9me2 compared with those of wild-
age, with about the same number of sites being hypermethylated type non-transgenic mice. Most importantly, similar changes
as hypomethylated with age. Compared with controls, 6% of were observed in histone transcription activating and repressive
genes featured on the array were differentially methylated in marks in the occipital cortex of AD samples (Lithner et al.,
AD samples, but the mean difference was relatively modest 2013).
(2.9%). Gene ontology analysis revealed a relationship between Although there are now treatments against AD, these are only
the main disease-specific methylation loci and several molecular palliatives and the pathology is currently incurable, whereby,

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there is an intense interest in the development of new potential et al. recently reported that reduction of folate and Vitamin B12
therapies. Epigenetic therapies have achieved some progress in in culture medium of neuroblastoma cell lines cause a reduction
the field of cancer, thus, several inhibitors of HDACs and DNA in SAM levels resulting in an increase of PSEN1 and BACE
methylation are approved for hematological malignances by the levels together with Aβ production. Conversely, the simultaneous
US Food and Drug Administration and have been in clinical use administration of SAM to the deficient medium restored the
for several years (Wu et al., 2008a). HDAC inhibitors (HDACIs) normal gene expression and reduced the Aβ levels (Fuso et al.,
are the most thoroughly studied and have shown acceptable 2007). Interestingly, the same group demonstrated that Vitamin
results in AD models. The inhibitors widely used in clinical B deficient-animals have shown that SAM inhibits the increase
research include trichostatin A (TSA), valproic acid (VPA), in progression of Alzheimer-like features (Fuso et al., 2012).
sodium 4-phenylbutyrate (4-PBA) and vorinostat (SAHA) (Wang This data suggests that folate or Vitamin B12-rich diets could be
et al., 2013). beneficial as therapy for AD patients; however, more studies are
In a study conducted by Su et al., VPA showed to inhibit Aβ needed.
production in HEK293 cell transfected with a plasmid carrying
the Swedish APP751 mutation. Interestingly, using the APPV717F PARKINSON’S DISEASE AND EPIGENETICS
transgenic model of AD, VPA was able to inhibit Aβ production Parkinson’s disease (PD) is the second most common
in the brain of mice at biologically relevant doses of 400 mg/kg neurodegenerative disorder after AD affecting approximately
(Su et al., 2004). In another study, VPA showed to decrease Aβ 1–2% of the population over the age of 65 and reaching a
production and alleviate behavioral deficits by inhibiting GSK- prevalence of almost 4% in those aged above 85. Resting tremor,
3β-mediated γ-secretase cleavage of APP in APP23 transgenic bradykinesia, rigidity, and postural instability are the main
mice (Qing et al., 2008). These results give us the idea about the clinical symptoms of the disease often accompanied by non-
possible contribution of epigenetic modifications in AD, which motor symptoms including autonomic insufficiency, cognitive
suggests that the drugs targeting epigenetic process may be of impairment, and sleep disorders (Thomas and Beal, 2011;
future therapeutic value (Wang et al., 2013). Coppedè, 2014). The brain of PD individuals is pathologically
As mentioned widely in scientific literature, the interaction characterized by a progressive loss of neuromelanin containing
between diet and epigenetics is the best documented in cancer dopaminergic neurons in the substantia nigra with the presence
pathology (Ho et al., 2009; Shu et al., 2010). Furthermore, of eosinophilic, intracytoplasmic inclusions termed as Lewy
based on evidence in support of epigenomics in regulating bodies (structures containing aggregates of α-synuclein as well
gene expression in stress-mediated AD risk factors, and the as other substances) and Lewy neurites in surviving neurons.
pathophysiology of AD, there has been growing interest in Unfortunately, only some improvements of the symptoms
examining whether diet and nutraceuticals targeting epigenomics are offered by current treatments based on levodopa and
may prevent, delay, or reverse the course of AD (Chiu et al., dopaminergic therapy, but there is no currently available
2014). In this regard, the Mediterranean diet rich in vegetables, treatment to avoid the progression of the disease (Thomas and
fruits and nuts, legumes, olive oil and fish with relative low Beal, 2011; Coppedè, 2014).
intakes of red meat has been suggested to reduce the risk for AD The vast majority of PD cases are idiopathic forms, likely
onset (Scarmeas et al., 2009; Frisardi et al., 2010). Other studies resulting from a combination of polygenic inheritance,
appoint that anti-oxidant-rich diets and consumption of dietary environmental exposures, and complex gene-environment
phytochemical such as caffeic acid, epigallocatechin-3-gallate, interactions imposed on slow and sustained neuronal dysfunction
Gingko biloba, resveratrol and phenolic compounds present in due to aging (Migliore and Coppedè, 2009). In a minority of
red wine slowed down disease progression by inhibiting Aβ the cases, PD is inherited as Mendelian trail, and studies in
production or amyloid aggregation in animal models (Kolosova PD families allowed the identification of at least 15 PD loci
et al., 2006). (PARK1-15) and several causative genes (Nuytemans et al., 2010).
It is well known that DNA methylation occurs within In addition, there are genes such as LRRK2, SNCA, MAPT and
folate/methionine/homocysteine (HCY) metabolism which GBA that are associated with sporadic PD without family history
uses micronutrients such as folate, methionine, choline and (Table 3; Coppedè, 2012).
betaine enzyme’s cofactors (Chouliaras et al., 2010; Wang et al., Most of the studies evaluating the role of epigenetic
2013). Diverse reactions occur and methionine is converted in pathogenesis have focused on the analysis of promoter
to S-adenosyl-methionine (SAM) and then converted to methylation of causative PD genes in post-mortem brains and
S-adenosyl-homocysteine (SAH), which in turn is converted peripheral blood; however, the role of DNA methylation and its
to HYC in a reversible reaction. Most important, SAM is the links to PD pathogenesis is currently unclear (Coppedè, 2012).
common methyl donor for DNA methylation that regulates Recent studies have shown that methylation of SNCA gene (the
gene expression and determines the chromosome conformation gene coding for α-synuclein) may be involved in disease via
(Sezgin and Dincer, 2014). An early study showed that SAM levels structural changes or overexpression of the protein, leading to
have been found to be decreased in post-mortem AD patients protein aggregation or via impaired gene expression (Ammal
(Morrison et al., 1996). Also, lower bioavailability of SAM causes Kaidery et al., 2013). In this regard, methylation of SNCA
changes in the expression of genes involved in APP metabolism intron 1 has been demonstrated to be associated with decreased
because this metabolite maintains the appropriate methylation of SNCA transcription, whereas reduced methylation at this site
genes involved in APP processing (Sezgin and Dincer, 2014). Fuso was found to be decreased in several brain regions, including

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from MPP+ toxicity in primary neuron-glia co-cultures in a

Table 3 | Epigenetic modifications of Parkinson’s disease related dose dependent manner (Wu et al., 2008b). Moreover, Kid
genes.
and Schneider demonstrated that vorinostat (another HDAC
inhibitor) protected two different dopaminergic neuronal cell
Gene Observation lines from apoptosis induced by MPP+ (Kidd and Schneider,
SNCA Reduced SNCA methylation in the substantia nigra of 2010), thus, the above results give us an idea about the alternative
PD patients. therapy by inhibiting HDACs in PD patients.
SNCA gene silencing mediated by histone methylation Although the etiology of PD is still unknown, multiple lines of
(Nalls et al., 2014). evidence support oxidative stress and mitochondrial dysfunction
Histone deacetylases inhibitors are neuroprotective as part of the pathogenic cascade. It would be interesting to
against α-synuclein mediated neurotoxicity in PD
know whether antioxidants-rich diets that have a helpful effect
animal models (IPDGC, 2011).
LRRK2 Mutant LRKK2 antagonizes miR-184 in Drosophila
in other degenerative disease such as AD (Kolosova et al., 2006),
melanogaster Parkinson’s disease models (IPDGC, could have the same effect in PD patients. To this regard, therapy
2011). focusing on nutrition, neutraceutical and antioxidants as part of a
Parkin let-7 family miRNAs were under-expressed in parkin healthy lifestyle might protect against cell death and thus delay
transgenic C.elegans (Asikainen et al., 2010) or halt disease progress; however, clinical and basic studies are
PARK16/lq32, Aberrant gene methylation in post-mortem Parkinson’s needed to prove such hypothesis (Bega et al., 2014).
GPNMB disease brains (IPDGC, 2011)

EPILEPSY AND EPIGENETICS

the subtancia nigra of sporadic patients, causing the increased Epilepsy is the third most common chronic brain disorder
expression of the SNCA gene (Jowaed et al., 2010). These results affecting 50 million of people worldwide (Aroniadou-Anderjaska
raise the possibility that the increased α-synuclein production et al., 2008). In this disorder, a variety of structures of the central
that is associated with PD may result from increased SNCA nervous system such as the hippocampus, the amygdala and the
expression, as a consequence of a decreased methylation state piriform cortex are susceptible to trigger electrical discharges that
of its gene (Ammal Kaidery et al., 2013). Additionally, it has contribute to brain damage and to the epileptogenic mechanism
been demonstrated that α-synuclein sequesters DNMT1 in the (Houser, 1990; Blümcke et al., 1999). These discharges promote
cytoplasm, leading to global DNA hypomethylation in PD and some morphological changes in the hippocampus such as, cellular
dementia with Lewy body in post-mortem brains, as well as in death in the CA1 and mossy fiber sprouting and dispersion of the
transgenic mouse models (Desplats et al., 2011). Conversely, the granule cell layer, alterations that are thought to be involved in
overexpression DNMT1 in both transgenic mouse models and the formation of recurrent excitatory circuits that contributes to
cellular cultures restore the nuclear level of the enzyme (Ammal seizure susceptibility (Heck et al., 2004).
Kaidery et al., 2013). In this regard, it is well known that seizures can give rise
The regulation of SNCA by epigenetic histone modifications to enduring changes that reflect alterations in gene expression
is yet to be studied in human PD brains. Studies in cell cultures patterns, contributing in this way to the hallmarks of epilepsy
and animal models of the disease, such as those induced by (Roopra et al., 2012). Moreover, some studies suggest that
mitochondrial toxins, including 1-methyl-4-phenylpyridinium these long-term changes mediated by seizures are mediated via
(MPP+ ), paraquat, rotenone, or those overexpressing human modulation of chromatin structure. One transcription factor in
α-synuclein, have revealed that α-synuclein translocates into particular, the repressor element 1-silencing transcription factor
the nucleus interacting with histones and inhibiting histone (REST/NRSF) has received a lot of attention due to its association
acetylation (Goers et al., 2003). Furthermore, in Drosophila with a great sub-set of genes associated with important processes
models, nuclear-targeted α-synuclein has been shown to bind to involved in neuronal homeostasis and because it may seem to
histones and reduce histone 3 acetylation through its association recruit a variety of proteins that elicit epigenetic modifications
with HDAC1 and SIRT2 (Kontopoulos et al., 2006). such as histone deacetylases and histone methyltransferases
In recent years, there has been considerable progress in (Bruce et al., 2004; Ballas and Mandel, 2005; Ballas et al., 2005;
the development of epigenetic-based drugs for the treatment Johnson et al., 2006; Pozzi et al., 2013). Some reports have
of neurodegenerative disorders such as PD. Such inhibitors shown that the induction of seizures in animal models induce
of HDACs and DNMTs are currently approved and available an overexpression in both REST/NRSF protein and mRNA levels
for clinical investigation (Xu et al., 2012). In this regard, (Formisano et al., 2007; Noh et al., 2012), suggesting that seizures
the targeted downregulation of SIRT2 has been shown to may cause an unbalance in the epigenetic modifications that
ameliorate α-synuclein toxicity and dopaminergic loss in flies control important processes of neuronal homeostasis. In contrast,
and in primary mesencephalic culture. Moreover, toxicity recent studies have shown that REST/NRSF is induced in the
associated with nuclear-targeted α-synuclein in both SH-SY5Y aging human brain regulating a network of genes associated
neuroblastoma cells and flies can be rescued by using HDACIs with stress resistance (Lu et al., 2014). This evidence suggests
(Outeiro et al., 2007), thus, HDACIs have been theorized to be that REST/NRSF regulates important processes in embryonic and
efficacious in neurodegenerative diseases (Harrison and Dexter, adult neuronal homeostasis and that the dysregulation of this
2013). In this regard, Wu et al. demonstrated that trichostain A transcription factor may impair epigenetic modifications that
(a well-known HDAC inhibitor), protects dopaminergic neurons regulate precisely an important network of genes contributing

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Landgrave-Gómez et al. Epigenetic mechanisms in neurological and neurodegenerative diseases

to distinct neurological/ neurodegenerative disorders such as

epilepsy or AD.
From a public health perspective, an alternative for the
treatment of epilepsy is a change of lifestyle or diet. These
methods have probably been used for over 2000 years and actually
metabolic regulation of neuronal excitability is increasingly
recognized as a factor in seizure pathologies and control
(Stafstrom et al., 2008; Yuen and Sander, 2014). In this way, FIGURE 4 | REST structure and their interactions with other proteins.
REST modulates the expression of its target genes by recruiting a host of
approximately half of the pharmacoresistant patients that have lysine-modifying enzymes. Numbers refer to amino acid residues. Colored
tried metabolism based therapies experience seizure control, molecules possess enzymatic activity.
opening the possibility of a strong link between the environments,
in this case nutrition, with this pathology (Greene et al., 2003;
Bough et al., 2006; Marsh et al., 2006; Patel et al., 2010). a lot of attention due to the possibility that it may control
These studies suggest that metabolism-based therapies such the expression of approximately 1,300 genes (Bruce et al., 2004;
as ketogenic diets, calorie restriction or intermittent fasting leads Johnson et al., 2006) that could be associated with a variety
to a range of biochemical and metabolic changes that induce a of processes that are important for neuronal homeostasis such
metabolic shift in pathways such as glycolysis, ketogenesis or beta as; synaptic transmission, synaptogenesis, excitability or even
oxidation, modifications that have been shown to increase seizure neurogenesis (Ballas and Mandel, 2005; D’Alessandro et al.,
thresholds and to decrease epileptogenesis in animal models 2009). REST modulates these genes in the nervous system
(Marsh et al., 2006; Patel et al., 2010). recruiting protein complexes that elicit different epigenetic
Moreover, recent studies have shown that environmental modifications (Figure 4; Roopra et al., 2012). Now it has been
inputs such as nutrition or exercise modulates cell metabolism, shown that REST is upregulated in pyramidal and dentate gyrus
and critical links between metabolism and epigenetic control neurons after status epilepticus induced by kainate (Palm et al.,
are beginning to emerge (Sassone-Corsi, 2013). For example, 1998) or even by ischaemic insults (Formisano et al., 2007;
the availability of specific metabolites such as acetyl-coenzyme Noh et al., 2012). Therefore, the upregulation of REST has
A (acetyl-coA) and nicotinamide adenine dinucleotide (NAD+ ) been previously considered as harmful in mature neurons. In
dictates the efficacy of histone deacetylases (Katada et al., 2012). contrast, recent studies have shown that induced expression
In this regard, it has been shown that beta hydroxybutyrate of REST/NRSF in mature hippocampal neurons is a protective
(β-HB), a ketone body that rises with ketogenic diets, during mechanism that modulates the inhibitory homeostatic control of
strenuous exercise or during fasting (Newman and Verdin, intrinsic excitability (Pozzi et al., 2013). Moreover, it has been
2014), acts as an endogenous inhibitor of histone deacetylases shown that REST/NRSF protects neurons from age-related toxic
linking in a precise way metabolism, epigenetics and epilepsy insults in AD and surprisingly these levels seems to be associated
(Shimazu et al., 2013). Thus, these studies strongly suggest that with preservation of cognitive function and increased longevity
the neuroprotective effects exerted by these kinds of therapies (Lu et al., 2014). These findings suggest that basal levels of
are not only mediated via metabolism alterations but also by REST/NRSF are necessary for a normal physiological condition
epigenetic modifications that may be involved in the expression in the adult brain and that elevated levels of REST/NRSF,
of an unknown sub-set of genes related to epilepsy. characteristic of epilepsy, may not be an epileptogenic factor,
Other interesting epigenetic modifications involved in rather it seems to be a homeostatic mechanism triggered by
epilepsy are methylation of DNA. In this field, Kobow et al. repeated hyper-excitability stimuli. This is an open issue that
using Methyl-seq, mapped for the first time the global DNA needs further investigation.
methylation patterns in chronic epileptic rats; they showed that
chronic epilepsy in animal models is characterized for a global CONCLUDING REMARKS
hypermethylation on DNA. Moreover, this group shows that As we state in this manuscript, one of the main factors
ketogenic diets diminish this increase of DNA methylation, that contributes to a variety of the most common diseases
suggesting that these kinds of therapies exert their effect not only is the environment. Many epigenetic enzymes are potentially
modulating metabolism, but also via epigenetic modifications susceptible to changes in the levels of a variety of metabolites,
(Kobow et al., 2013). More importantly, it opened the possibility and are, hence, poised to respond to changes on environment. In
for the development of new metabolism based therapies designed this sense, it has been demonstrated that changing our lifestyle
to regulate these epigenetic modifications contributing to the could mediate great beneficial effects regulating a network of
inhibition of the seizure threshold in epilepsy. genes via the modulation of chromatin structure, providing new
alternatives for the prevention of many diseases.
THE ROLE OF REST/NRSF IN NEUROLOGICAL DISORDERS Different questions remain to be answered including which
A growing body of literature suggests that long-term changes epigenetic modifications are implicated in neurological disorders,
in gene transcription associated with a lot of neurological how does the environment mediate these changes, could
disorders are mediated via modulation of chromatin structure. pharmacological inhibitors of these modifications provide an
One transcription factor in particular, REST/NRSF (repressor alternative for treating disease, and so on. Increasing evidence
element 1-silencing transcription factor) (Figure 4), has received on this field had taught us that these modifications are capable

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Landgrave-Gómez et al. Epigenetic mechanisms in neurological and neurodegenerative diseases

of regulating great networks of genes that can influence a variety Borrelli, E., Nestler, E. J., Allis, C. D., and Sassone-Corsi, P. (2008). Decoding the
of physiological processes important for overall homeostasis and epigenetic language of neuronal plasticity. Neuron 60, 961–974. doi: 10.1016/j.
neuron.2008.10.012
that the disruption of this balance can increase the risk of disease.
Bottiglieri, T., Godfrey, P., Flynn, T., Carney, M. W., Toone, B. K., and Reynold, E. H.
From a public health perspective, we need to better understand (1990). Cerebrospinal fluid S-adenosyl-methionine in depression and dementia:
which alterations in metabolism and in chromatin structure effects of treatment with parenteral and oral S-adenosyl-methionine. J. Neurol.
cause disease and, maybe, it will be possible to design rationale Neurosurg. Psychiatry 53, 1096–1098. doi: 10.1136/jnnp.53.12.1096
metabolism-based therapies that could function as alternative Bough, K. J., Wetherington, J., Hassel, B., Pare, J. F., Gawryluk, J. W., Greene, J. G.,
et al. (2006). Mitochondrial biogenesis in the anticonvulsant mechanism of the
treatments of these kinds of disorders.
ketogenic diet. Ann. Neurol. 60, 223–235. doi: 10.1002/ana.20899
Bruce, A. W., Donaldson, I. J., Wood, I. C., Yerbury, S. A., Sadowski, M. I.,
ACKNOWLEDGMENTS Chapman, M., et al. (2004). Genome-wide analysis of repressor element 1
silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF)
This work was supported by grants from Programa de
target genes. Proc. Natl. Acad. Sci. U S A 101, 10458–10463. doi: 10.1073/pnas.
Apoyo a Proyectos de Investigación e Innovación Tecnológica, 0401827101
DGAPA-PAPIIT (IN211913) and Consejo Nacional de Ciencia y Champagne, F. A., and Curley, J. P. (2009). Epigenetic mechanisms mediating the
Tecnología, CONACyT (239594). The authors want to thank Mrs. long-term effects of maternal care on development. Neurosci. Biobehav. Rev. 33,
Josefina Bolado for editing this English-language text chapter. 593–600. doi: 10.1016/j.neubiorev.2007.10.009
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