2013 - Lu Et Al - DNA Methylation, A Hand Behind Neurodegenerative Diseases

REVIEW ARTICLE
published: 05 December 2013

AGING NEUROSCIENCE doi: 10.3389/fnagi.2013.00085
DNA methylation, a hand behind neurodegenerative

diseases
Haoyang Lu † , Xinzhou Liu † , Yulin Deng and Hong Qing *
School of Life Science, Beijing Institute of Technology, Beijing, China
Edited by: Epigenetic alterations represent a sort of functional modifications related to the genome
Isidro Ferrer, University of that are not responsible for changes in the nucleotide sequence. DNA methylation is one
Barcelona, Spain
of such epigenetic modifications that have been studied intensively for the past several
Reviewed by:
decades. The transfer of a methyl group to the 5 position of a cytosine is the key feature
Andrea Fuso, Sapienza University of
Rome, Italy of DNA methylation. A simple change as such can be caused by a variety of factors,
Jose V. Sanchez-Mut, Bellvitge which can be the cause of many serious diseases including several neurodegenerative
Biomedical Research Institute, Spain diseases. In this review, we have reviewed and summarized recent progress regarding
*Correspondence: DNA methylation in four major neurodegenerative diseases: Alzheimer’s disease (AD),
Hong Qing, School of Life Science,
Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis
Beijing Institute of Technology,
5 South Zhongguancun Street, (ALS). The studies of these four major neurodegenerative diseases conclude the strong
Haidian District, Beijing 100081, suggestion of the important role DNA methylation plays in these diseases. However,
China each of these diseases has not yet been understood completely as details in some areas
e-mail: hqing@bit.edu.cn
† These authors have contributed
remain unclear, and will be investigated in future studies. We hope this review can provide
equally to this work.
new insights into the understanding of neurodegenerative diseases from the epigenetic
perspective.
Keywords: DNA methylation, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral
sclerosis
INTRODUCTION made in the study of DNA methylation in four major neurode-

Epigenetic refers to the study of mitotically or meiotically her- generative diseases: Alzheimer’s disease (AD), Parkinson’s disease
itable changes in gene functions that cannot be explained by (PD), Huntington’s disease (HD), and amyotrophic lateral sclero-
changes in DNA sequence. In most cases, it acts as the her- sis (ALS). We will discuss in depth the relationship between DNA
itable regulation of DNA transcription by DNA methylation, methylation and neurodegenerative diseases, as well as the causal
histone modification and expression of noncoding RNAs. Since and consequential effect of DNA methylation in these diseases.
R. D. Hotchkiss (Hotchkiss, 1948) discovered that DNA can be
methylated at the 5-position of cytosine in 1948, the mysteri- THE PRINCIPLE OF DNA METHYLATION
ous veil on epigenetics has been gradually lifted. A study of in As the most widely characterized epigenetic modification, DNA
discordant twins pointed out that epigenetics can make a differ- methylation in eukaryotes is found nearly exclusively at cytosine
ence, even in a pair of monozygotic twins (Fraga et al., 2005). residues. A methyl group is added at the 5-position of cyto-
Fraga et al. uncovered that even if sharing a common geno- sine before a guanine and gene silencing is frequently associated
type, twins still showed different penetrance of various diseases with this modification. This dinucleotide unit is always written
such as neurological disorders. Among epigenetic mechanisms, as CpG, representing a combination of a cytosine, the follow-
DNA methylation is a crucial epigenetic marker that has been ing guanine and a phosphate group between them. Regions with
most widely studied. Alterations of DNA methylation are involved high concentration of CpGs are called CpG islands, which usu-
in many human diseases including cancer and neurological ally locate in promoter region of genes, a place where most CpGs
disorders. in the human genome exist. Cytosines are usually not methy-
Neurodegenerative diseases are one kind of neurological dis- lated in CpG islands, but for some particular functions, such as
eases featuring the progressive loss and even final death of X chromosome inactivation, methylation of CpG islands is also
neurons. The specific causes and pathological mechanisms of required. On the other hand, predominantly located in repetitive
neurodegenerative diseases have not been completely understood. or centromeric sequences, CpGs outside CpG islands are usu-
Recently, a large amount of evidence have emerged to show a ally methylated (Reik et al., 2001; Bird, 2002). Data showed that
shared non-Mendelian property between DNA methylation and unmethylated regions of the genome are protected from DNA
neurodegenerative diseases, a connection that has peaked research methylation by a combination of factors involving very high CpG
interest for over two decades. densities and histone modifications, while the remaining bulk of
The main purpose of this review is to provide an overview on the genome is methylated as the default state (Edwards et al.,
the involvement of DNA methylation in the pathology of neu- 2010). CpG methylation within promoter and intragenic sites
rodegenerative disease. We will begin by outlining the concept have been extensively studied and recent interest have also arisen
of DNA methylation, then focus intensively on recent progress regarding non-CpG methylation, which refers to the methylation
Frontiers in Aging Neuroscience www.frontiersin.org December 2013 | Volume 5 | Article 85 | 1

Lu et al. DNA methylation and neurodegenerative diseases
that occurs at cytosines of non-CpG dinucleotides, such as CA, ability to remember new information. The patient’s cognitive and
CT, or CC. While CpG methylation can occur whenever gene functional abilities decline as the disease progresses. Extracellular
silencing is needed during the life span of a cell, non-CpG methy- neuritic plaques, intracellular neurofibrillary tangles and neu-
lation is dominantly present in embryonic stem cells (Haines ronal loss are the main pathological hallmarks in AD brains. AD
et al., 2001; Dodge et al., 2002; Lister et al., 2009) as well as in is ultimately fatal and has become the sixth leading cause of death
neural development (Lister et al., 2013). in the United States (Thies et al., 2013).
More specifically, 5-methylcytosine (5mC) is produced by The cause of AD is still unclear. Numerous genetic and envi-
transferring a methyl group from an S-adenosyl-L-methionine ronmental risk factors are involved in the etiology and pathogen-
(SAM) to the cytosine with the help of DNA methyltrans- esis of AD, including alterations in the expression of thousands
ferases (DNMTs) (Figure 1). Five kinds of proteins—DNMT1, of genes, amyloid β-peptide (Aβ) deposition, tau hyperphospho-
DNMT2, DNMT3a, DNMT3b, and DNMT3L are major mem- rylation, inflammation, oxidative stress, energy metabolism, and
bers of DNMT family (Bestor, 2000). The functions of DNMT aberrant re-entry into the cell cycle/apoptosis. It’s worth noting
in DNA methylation can be divided into maintenance methy- that when Aβ-inducing mutations are absent, these molecular and
lation and de novo methylation. DNMT1 is involved in main- genetic factors do not have absolute penetrance in causing the
tenance methylation, which refers to the process of copying disorder (Mastroeni et al., 2011).
DNA methylation profiles to the daughter strands during DNA Two dominant hypotheses to explain the disease are Aβ
replication. DNMT3a and DNMT3b are de novo methyltrans- hypothesis and tau hypothesis. Redundant Aβ is considered a
ferases that establish DNA methylation patterns in early devel- main contributor to the dysfunction and degeneration of neu-
opment. DNMT3L has no catalytic activity but can assist the de rons that occurs in AD. Aβ, a 38–43 amino acid peptide, is gained
novo methyltransferases by improving their ability of binding to from sequential β- and γ-secretase cleavages of amyloid-β pre-
DNA and stimulating their activity. Instead of methylating DNA, cursor protein (APP). When the cleavage site lies within the Aβ
DNMT2 was shown to methylate the anticodon loop of aspartic sequence, another APP processing enzyme, α-secretase, precludes
acide transfer RNA at cytosine-38 (Goll et al., 2006). Recognizing Aβ formation. Beta-site APP cleaving enzyme 1 (BACE1) is the
and binding of methyltransferases to 5-methylcytosines requires major β-secretase in the brain. γ-Secretase consists a minimum 4
methyl-CpG binding domain (MBD) proteins, which are MeCP2, proteins: presenilin 1 (PS1) or presenilin 2 (PS2), nicastrin (Nct),
MBD1, MBD2, MBD3, and MBD4 in mammals (Fatemi and presenilin enhancer 2 (Pen2), and anterior pharynx defective 1
Wade, 2006). In addition to 5mC, there exists another kind of (Aph-1) (Chow et al., 2010). Another hypothesis, the tau hypoth-
methylated cytosine, 5-hydroxymethylcytosine (5hmC), which is esis, is based on the hyperphosphorylation of tau in patients
consequence of the oxidation of 5mC that is catalyzed by the ten- with AD. How phosphorylation influences tau function is only
eleven translocation (TET) proteins. In turn, 5hmC also can be poorly understood, but it negatively regulates the binding of tau
deaminated to 5mC via the mediation of AID/APOBEC family to microtubules. Hence, functions of tau such as microtubule
proteins. 5hmC in mammalian DNA was first described in the stabilization and the regulation of axonal transport may be com-
early 1970s (Penn et al., 1972), however, it has been poorly stud- promised, possibly contributing to disease. Moreover, interactive
ied until recently when studies found that 5hmC is present in enhancements between Aβ and tau were also proposed recently
mouse neurons as well as in embryonic stem cells (Kriaucionis (Ittner and Gotz, 2011).
and Heintz, 2009; Tahiliani et al., 2009). Since then, it has been AD can be generally categorized into two divisions. Less than
substantiated that 5hmC can influence the regulation of gene 2% of AD cases are early-onset Alzheimer’s disease (EOAD),
expression, and the conversion of 5mC to 5hmC may contribute which onsets prior to age 60 with genetic mutations in APP, prese-
to DNA demethylation that, in most cases, associates with gene nilin 1, or presenilin 2 genes. Mutations in these genes dysregulate
activation (Bhutani et al., 2011; Guo et al., 2011a). the APP pathway and directly lead to Aβ plaque accumulation,
DNA methylation works in harmony with histone acetylation a major pathological hallmark of AD. Other cases which are
to control memory formation and synaptic plasticity (Miller et al., sporadic and manifest symptoms after age 60, are termed late-
2008), and it also has a possible impact on genetic and neuronal onset Alzheimer’s disease (LOAD). At least one apolipoprotein
function affecting behaviors (Day and Sweatt, 2010). Besides, 4 allele (APOE-4) is found in approximately 50–65% of LOAD
the connection among DNA methylation, chromatin structure cases, while the global population prevalence of the allele is only
and gene silencing has been extensively studied for many years, approximately 20–25% (van der Flier et al, 2011).
and the gene silencing is thought to be an epigenetic interven-
tion on neurodegenerative diseases like AD (Scarpa et al., 2006). DNA METHYLATION MODIFICATION EVIDENCE IN AD
Therefore, we can believe that there is a very strong potential link DNA methylation modifications related to AD can be divided
between DNA methylation and neurodegenerative diseases as we into two groups: global DNA methylation modifications and
will talk about below. gene-specific DNA methylation modifications. Global DNA
hypomethylation and specific gene hypermethylation are the
DNA METHYLATION AND ALZHEIMER’s DISEASE overall phenomenon among studied AD cases.
INTRODUCTION TO ALZHEIMER’S DISEASE
AD is the most common form of dementia, which brings acute Global methylation modification and AD
suffering to its patients. Eleven percent of people age 65 or older Most studies support the view that on the whole-genome
and 32% of people age 85 or older are afflicted by this disease. The scale, the DNA methylation level in AD cases is lower than in
general symptom pattern begins with the gradually worsening of comparison with normal individuals. Direct evidence came from

FIGURE 1 | Metabolic pathway of DNA methylation. HCY/SAM cycle substrates and products are shown in black. Red line marks the step where the
ensures the continuous transport of methyl group from SAM to cytosine, pathway can be blocked by deficiency of folate, vitamin B6 and vitamin B12 , and
providing the raw material of DNA methylation. Enzymes are shown in red while such block results in HCY accumulation and other biological effects.
studies in monozygotic twins. A postmortem study of rare sets AD patients of far-going epigenetic markers and regulators in
of monozygotic twins discordant for AD reported significantly neurons from control entorhinal cortex layer II, consistent with
reduced levels of DNA methylation in temporal neocortex neu- the high vulnerability of this brain region to AD pathology. The
ronal nuclei of the AD twin, which provided the potential for AD result indicates that global DNA and RNA methylation status are
discordancy in spite of genetic similarities. With specific mark- significantly diminished in AD in this region (Mastroeni et al.,
ers, decrement in DNA methylation was observed in AD reflected 2010). This trend of global hypomethylation was further con-
among neurons, reactive astrocytes, and microglia (Mastroeni firmed in a more recent and direct study, in which decrements
et al., 2009). Research also recognized a dramatic decrease in of 5mC and 5hmC were shown in AD patients’ hippocampus by

a quantitative immunohistochemical method (Chouliaras et al., It has also been reported that BACE1 expression can be
2013). A similar result was also shown in a cell line. Using the AD upregulated via demethylation of at least two CpG sites at posi-
model cell line H4-sw, which harbors the Swedish mutation and tion +298 and +351 in the 5 -untranslated region in BV-2
produces high levels of the toxic form Aβ, global methylation sta- microglial cells (Byun et al., 2012).
tus were analyzed. Among the total 6296 differentially methylated
CpG sites, 23% were shown to be hypermethylated while others Aβ-degradation-related genes. Aβ peptides are proteolytically
were hypomethylated (Sung et al., 2011). degraded within the brain mainly by neprilysin (NEP) (Iwata
However, such a conclusion is not supported by all the et al., 2000) and insulin-degrading enzyme (IDE, insulysin)
evidence. For instance, a postmortem human frontal cortex (Kurochkin and Goto, 1994). The endolytic degradation of Aβ
genome-wide DNA methylation study also showed general and peptides within microglia by NEP and related enzymes is sig-
mild discordant DNA methylation in LOAD-diseased tissue inde- nificantly enhanced by apolipoprotein E (ApoE). Similarly, Aβ
pendent of the age factor, while both hypomethylation and extracellular degradation by IDE is facilitated by ApoE (Jiang
hypermethylation were found (Bakulski et al., 2012). Moreover, et al., 2008). There are three major isoforms of ApoE: ApoE2,
another postmortem human frontal cortex study showed a trend ApoE3, and ApoE4. Among them, ApoE3 is the most common
of global DNA hypermethylation in AD cases (Rao et al., 2012). isoform in the population, while ApoE4 has been shown to confer
It is noteworthy that DNA hypomethylation tendency in AD is dramatically increased risk for LOAD (Roses et al., 1995).
mainly supported by immunoassays, but the opposite tendency It has been reported that Aβ causes NEP promoter region
has been observed through bisulfite treatment, which is a direct hypermethylation, which consequently suppresses NEP’s expres-
interrogation of DNA. sion in mRNA and protein levels, reduces the Aβ clearance and
probably elevates Aβ accumulation. This could be part of a vicious
Gene specific DNA methylation modification and AD cycle which plays a role in the pathophysiology of AD (Chen et al.,
Researchers have also traced the methylation modification of a 2009). Sortilin-related receptor (SORL1, also known as SORLA,
number of specific genes, which are believed to be related to AD. SORLA1, or LR11) is a neuronal ApoE receptor. Its connection
Such studies usually concentrate on the gene promoter region, in with AD is based on its reduction in AD brains and its ability to
which DNA methylation regulates the expression of genes. We will lower Aβ levels (Offe et al., 2006). The SORL1 gene showed dif-
divide these genes into six sections and introduce findings in each ferences in its expression among peripheral blood leukocytes, and
section. it may act as a marker of aging in this tissue. It has been shown
that SORL1 promoter DNA methylation could serve as one of the
Aβ-generation-related genes. APP, PS1, and BACE1 play crucial mechanisms in charge of the differences in expression observed
roles in the generation of Aβ. Therefore, the promoter regions of between blood and brain for both healthy elders and AD patients
their genes have been studied in many different researches. groups (Furuya et al., 2012a).
Recent results overall suggest that there is no correlation
between APP methylation modification and AD. A large-scale Tau-related genes. Activity and expression level of glycogen syn-
postmortem study involving frontal cortex and hippocampus thase kinase 3β (GSK3β), the major kinase that phosphorylates
found no difference in APP gene promoter region methylation tau in the brain, are increased in AD brains (Nicolia et al., 2010).
among all stages of AD patients and healthy controls. The preser- A study in human neuroblastoma SK-N-BE cell line and
vation of DNA methylation status in postmortem brain samples TgCRND8 mouse showed that GSK3β gene’s promoters can be
was also confirmed (Barrachina and Ferrer, 2009). Another post- hypomethylated by inhibiting methylation activity through B
mortem study focusing on the cortex and cerebel observed no vitamin deficiency and such hypomethylation results in the over-
methylated CpG in APP promoter regions in any familial AD expression of GSK3β (Nicolia et al., 2010). It was also reported
patients and their healthy comparisons (Brohede et al., 2010). that inhibition of GSK3β reduces the expression of DNMT3A
However, a study in SH-SY5Y cell lines indicated that the pro- and causes hypomethylation of related genes in mouse embryonic
moter of APP is capable to be hypomethylated (Guo et al., stem cells (Popkie et al., 2010).
2011b).
The situation of PSEN1 (the gene encoding PS1) seems more Genes involved in metabolic pathways. Another finding is that
apparent, since almost every study in this field reports PSEN1 rare haplotypes may be associated with the risk of AD through a
promoter hypomethylation and the resulting overexpression of possible modulation of the methylation of the ornithine transcar-
PSEN1 as factors leading to AD. Firstly, studies in neuroblas- bamylase (OTC) promoter. In spite of being mostly speculative,
toma cell lines (Fuso et al., 2005) and mouse (Fuso et al., 2008, it might suggest a deregulation of urea cycle in AD (Bensemain
2011b) showed that PSEN1 can be overexpressed through DNA et al., 2009).
hypomethylation. Further investigations in mouse ruled out the
possibility that hypomethylation of PSEN1 promoter is the con- Ribosomal DNA (rDNA). Ribosomal deficits are verified in mild
sequence of amyloid production (Fuso et al., 2012a). Finally, sim- cognitive impairment (MCI), which often represents an early
ilar hypomethylation was observed in postmortem study (Wang stage AD as well as the potential of advanced AD (Ding et al.,
et al., 2008). However, it should be noted that almost all papers 2005). Although an early study didn’t detect any differential
reporting PSEN1 hypomethylation in AD came from the same methylation pattern of rDNA genes in total peripheral blood
laboratory, and these results need to be validated by independent cells in elderly and AD subjects (Speranca et al., 2008), it was
laboratories. reported later that the rDNA promoter become hypermethylated

in studied AD cerebrocortical samples, suggesting that rDNA Although more than 90% of the cases can be interpreted as
hypermethylation could be implicated in AD (Pietrzak et al., sporadic PD, the greatest insights into PD etiology have come
2011). from the study of familial forms. In recent years, mutations in
six genes have been identified as causes of PD: SNCA (which
Other genes. The complexity of AD and epigenetics leads to encodes α-synuclein), PARK2 (parkin), PINK1 (PTEN-induced
an endless stream of research. One study suggested that behav- kinase protein 1), UCHL1 (ubiquitin carboxyl-terminal hydrolase
ioral and psychological symptoms in dementia patients may be isozyme L1), DJ1 (protein DJ-1), and LRRK2 (leucine-rich repeat
caused by the methylation disturbance of circadian gene (Liu serine/threonine-protein kinase 2). The hallmark neuropatholog-
et al., 2008). In addition, DNA methylation status of repetitive ical sign of PD is the presence of fibrillar aggregates of misfolded
elements long interspersed element-1 (LINE-1) was shown to α-synuclein called Lewy bodies, which accumulate in the same
be increased in AD patients compared with healthy volunteers sites where neuronal loss is found (Urdinguio et al., 2009).
(Bollati et al., 2011). Moreover, various potential functions of Although PD is less studied than AD in terms of the relation
neuroglobin (NGB) have been exhibited and found to be able to epigenetics, this section aimed to review the interrelation of
to reduce the severity of stroke and AD (Khan et al., 2007). PD and DNA methylation is organized into two parts. First part
A 5-aza-2 -deoxycytidine (a methyltransferase inhibitor) treat- is exploring what genetic factors of PD pathogenesis might be
ment analysis indicated that DNA methylation/demethylation affected by DNA methylation, and the other one is aimed to show-
may be involved in regulating NGB tissue-specific expression ing how environmental factors could get involved in the alteration
(Zhang et al., 2011). Another separate research implies that long of DNA methylation leading to PD.
telomeres with hypomethylation tend to shorten faster, while cells
bearing short telomeres with hypomethylation tend to enter into GENETIC FACTORS, DNA METHYLATION AND PD
a senescent state under elevated OS stress in AD more easily. DNA methylation regulation of α-synuclein
It has been validated that this trend can be reversed by vita- Considering that α-synuclein makes a major contribution to the
min E (Guan et al., 2012). Rao et al. reported hypomethylated formation of Lewy bodies and even to the entire pathogenesis of
cyclooxygenase-2 (COX-2) (one of the arachidonic acid (AA) cas- PD, we start from discussion on impact DNA methylation has on
cade markers) and brain-derived neurotrophic factor (BDNF) α-synuclein.
promoter regions in AD brain, while the promoter region of An earlier study revealed that the DNA methylation pattern
cAMP response element-binding protein (CREB), which regu- within the α-synuclein (SNCA) gene promoter region was altered
lates the transcription of BDNF, was shown to be hyperme- in the blood samples of patients with alcoholism, which was
thylated. Their study also found a significant increase in DNA significantly associated with their increased homocysteine lev-
methylation at the promoter region of synaptophysin (SYP) and els (Bonsch et al., 2005). This is the first study, to the best
decreased methylation of the NF-kB promoter CpG region in the of our knowledge, to show a correlation between DNA methy-
AD (Rao et al., 2012). S100A2 is a member of the S100 family lation and α-synuclein in certain syndromes. Later on, it has
of calcium binding proteins while SORBS3 encodes a cell adhe- been reported that the methylation of human SNCA intron 1
sion molecule expressed in neurons and glia. The decrement decreased gene expression while inhibition of DNA methyla-
of S100A2 and increment in SORBS3 CpG methylation in AD tion activated its expression in the brains of PD patient (Jowaed
brains were reported from a postmortem study (Siegmund et al., et al., 2010), which further strengthens the link. Although analysis
2007). of postmortem brain did not reveal regional specific methyla-
Some other genes involved in AD were also investigated, but tion differences in the putamen and anterior cingulate between
no DNA methylation differences have been found in these genes. PD and healthy individuals, methylation was found specifi-
These genes include synaptosomal-associated protein 25 (SNAP- cally and significantly reduced in the substantia nigra of PD
25) (Furuya et al., 2012b), SIRT3, SMARCA5, CDH1 (Silva et al., patients (Matsumoto et al., 2010). In addition, single CpG analy-
2008), 2 ,3 -cyclic-nucleotide 3 -phosphodiesterase (CNP), and sis reflected fluctuating methylation levels at different locations
dihydropyrimidinase-like 2 (DPYSL2) (Silva et al., 2013). in various brain regions and LBD stages, even if the overall
methylation levels in the promoter and intron 1 of α-synuclein
DNA METHYLATION AND PARKINSON’S DISEASE gene were reported to be similarly low both in Lewy body dis-
INTRODUCTION TO PARKINSON’S DISEASE ease (LBD) patients and controls(de Boni et al., 2011). These
PD is the second most common neurodegenerative disorder after results suggest a potential role of DNA methylation in α-synuclein
AD. According to the PD Foundation, about 1 million people neuropathogenesis.
in the United States and more than 4 million people worldwide Unfortunately, in the blood cell sample of a PD patient with
are affected with this disease. The prevalence of PD in industrial- heterozygous SNCA A53T mutation, α-synuclein expression was
ized countries is generally estimated at about 1–2% of population found to be monoallelic because of epigenetic silencing of the
over 60 years of age, and increases to 3–5% in people above 85 mutated allele through histone modification instead of DNA
years old. This neurodegenerative disorder is characterized by the methylation (Voutsinas et al., 2010). Rather than altering DNA
progressive loss of substantia nigra dopaminergic neurons and methylation, α-synuclein negatively regulated PKC-delta expres-
striatal projections, causing the typical symptomatology: muscle sion in human dopaminergic neurons by reducing histone mod-
rigidity, bradykinesia, tremor, and postural instability (de Lau and ification (Jin et al., 2011). Moreover, no differential methylation
Breteler, 2006). of SNCA was observed in white blood cell DNA of PD patients

compared to the neurologically normal controls (Richter et al., that altered promoter methylation may contribute to the aberrant
2012). expression of clock genes in PD (Lin et al., 2012). A genome-wide
Nonetheless, the interaction of DNMT and α-synuclein has methylation analysis of PD with quantities DNA methylation
also been tested. Reduction of nuclear DNMT1 levels was levels found reduced methylation of the cytochrome P450 2E1
observed in postmortem brain samples from PD patients and in gene in PD patients’ brains compared to the controls, which
the brains of α-synuclein transgenic mice, underlying a mecha- suggests that epigenetic variants inde-toxifying enzymes, such
nism in which DNMT1 might be excluded from the nucleus by as cytochrome genes, may add to PD susceptibility (Kaut et al.,
α-synuclein, and the segregation of DNMT1 further resulted in 2012). Mesodiencephalic dopaminergic (mdDA) neurons, located
hypomethylated CpG islands upstream of α-synuclein(Desplats in the ventral mesodiencephalon, are involved in severely affected
et al., 2011). neurodegenerative diseases such as PD. Emerging evidence shows
Overall, these results indicate that there is a good chance that that epigenetic mechanisms including DNA methylation play an
DNA methylation is involved in the regulation of α-synuclein important role in mdDA development, maturation and mainte-
gene expression, even if its specific role still remains to be further nance (van Heesbeen et al., 2013). Furthermore, other specific
clarified. genomic regions were also examined on the methylation level. For
example, researchers have found that the number of short telom-
DNA methylation in other genes related to PD eres with constant subtelomeric methylation status was smaller
In addition to α-synuclein, several other genes also have been in peripheral leukocytes from Japanese PD patients compared to
examined to find whether they are associated with PD in a the healthy controls (Maeda et al., 2009). Although, based on the
DNA-methylation-regulated way. limited number of studies in this field, we cannot come up with
Tumor necrosis factor α (TNF-α) is a critical inflammatory a meaningful conclusion from these findings, but at least there
cytokine and increased TNF-α is associated with dopaminergic might be a bold hypothesis that DNA methylation associates with
cell death in PD. It has been suggested that a lesser extent of PD through a variety of genetic pathways.
methylation of the TNF-α promoter in human substantia nigra
cells could uphold the increased vulnerability of dopaminergic ENVIRONMENTAL FACTORS AND DNA METHYLATION IN PD
neurons to TNF-α regulated inflammatory reactions (Pieper et al., Environment can significantly affect the risk and progression
2008). Because TNF-α overexpression induces apoptosis in neu- of neurodegenerative disorders including PD. Here we synthe-
ronal cells and TNF-α levels were rather high in the cerebrospinal sized published studies focused on the interaction between DNA
fluid of PD patients (Mogi et al., 1996), we can speculate that methylation and environmental factors in PD cases.
DNA methylation might be the reason for such overexpression Elevated plasma homocysteine levels have been documented
of TNF-α. As is well known, the parkin gene plays a relatively in PD individuals (O’Suilleabhain et al., 2004). A further increase
important part in the emergence and development of PD. The in plasma homocysteine levels of blood cell samples was observed
methylation levels of the parkin gene promoters were analyzed in in individuals with both PD and the MTHFR C677T mutation
samples from PD patients heterozygous for parkin mutations, PD (Brattstrom, 2001). PD patients undergoing regular treatment
patients without parkin mutations, and normal controls, however, with L-Dopa had higher plasma homocysteine concentrations
no significant difference was observed among the three groups, relative to healthy controls, indicating a possible methylated
indicating that parkin promoter methylation alone is unlikely to catabolism of the drug (Blandini et al., 2001). Dietary folate
impact the pathogenesis and development of PD (Cai et al., 2011). deficiency and elevated homocysteine levels have been found
Ubiquitin c-terminal hydrolase L1 is a member of one subfamily to be harmful to dopaminergic neurons in mouse models of
of deubiquinating enzymes that remove ubiquitin from ubiquiti- PD (Duan et al., 2002). A recent study found out that hall-
nated substrates in the ubiquitin proteasome degradation system. marks of neurodegeneration such as APP and α-synuclein were
Dysfunction of UCHL-1 has been implicated in the pathogen- related to markers of methylation like SAM and its down-
esis of neurodegenerative disorders, including PD. The UCHL1 stream byproduct, S-Adenosyl-L-homocysteine (SAH) in indi-
promoter was found hypermethylated in diverse types of cancer viduals with PD (Obeid et al., 2009). A higher SAM/SAH ratio,
(Kagara et al., 2008; Yu et al., 2008), however, analysis of UCHL1 which indicates a higher methylation potential, was linked to
promoter in the hippocampus and frontal cortex of PD patients better cognitive function. Note that the SAM/SAH ratio is a
and controls displayed no significant differences in CpG methy- significant positive predictor of DemTect scores in PD patients
lation between these two groups (Barrachina and Ferrer, 2009). and DemTect is a cognitive screening instrument sensitive to
A large-scale sequencing analysis of postmortem brain samples the early cognitive symptoms of dementia including AD and PD
identified methylation and expression changes associated with PD (Kalbe et al., 2004).
risk variants in PARK16/1q32, GPNMB/7p15, and STX1B/16p11 Telomeric dysfunction has been discovered to be associated
loci, suggesting that some other PD-related genes could also be with development of age-related pathologies, and similarly to
epigenetically modified in PD brains (Plagnol et al., 2011). AD, shortened telomeres were found present in patients with PD
More recently, it was reported that the expression of clock (Guan et al., 2008). Telomere length is epigenetically regulated by
genes was altered in both PD patients and in animal models of the DNA methylation, which in turn could be modulated by folate
disease (Cai et al., 2010; Hood et al., 2010). Promoter methylation status. In human, telomere length has been reported to be associ-
analysis of seven clock genes in blood samples of PD revealed that ated with folate status (Paul et al., 2009). Plus, various nutrients
most clock gene promoters were short of methylation, suggesting also showed potential to influence regulation of telomere length,

e.g., folate, via its role in epigenetic status of DNA methylation thus responsible for the expression of HD (Farrer et al., 1992).
and histone modification (Paul, 2011). Although a comparison between HD patients and normal con-
Besides, environmental exposure, including paraquat, is trols showed no strong relevance between methylation and onset
believed to be a risk for PD. Interestingly, a pretreat- age of the disease, a significant association of the patient’s age with
ment of PC12 with 5-aza-2 deoxycytidine, a DNMT inhibitor, demethylation at D4S95 was found (Reik et al., 1993). A PCR-
sensitizes cells to paraquat exposition. Similar results were amplication of synthetic oligodeoxyribonucleotides revealed that
obtained using dopaminergic cells and treatments of MPP(+), cytidine methylation could have an impact on the expansion
6-hydroxydopamine and rotenone, (Wang et al., 2013) suggest- of triplet repeat sequences (Behnkrappa and Doerfler, 1994).
ing that DNA methylation might modulate the effect of these Another finding that genome-wide demethylation could acceler-
toxins and might play a role in PD susceptibility (Kong et al., ate instability of CTG/CAG trinucleotide repeats in mammalian
2012). These findings underlie a possible mechanism in which cells, implies that changes in methylation patterns during epi-
environment influences pathology of PD via DNA methylation genetic reprograming may trigger the intergenerational repeat
modification. Nevertheless, since data presented so far are too expansions, leading to neurological diseases like HD (Gorbunova
insufficient to substantiate any hypothesis, further solid findings et al., 2004).
are very necessary and helpful to arrive at a reliable conclusion. It has been discovered that there is a region of highly unsta-
ble CAG repeats at the human spinocerebellar ataxia type 7
DNA METHYLATION AND HUNTINGTON’S DISEASE (SCA7) locus, and this region contains binding sites for CTCF,
INTRODUCTION TO HUNTINGTON’S DISEASE a regulatory factor involved in genomic imprinting, chromatin
HD, or Huntington’s chorea, is the most common genetic cause remodeling, and DNA conformation change (Filippova et al.,
of chorea in high-income countries, with a prevalence of about 2001). Recently, an investigation in transgenic mice model found
one in 10,000 people. This lethal neurodegenerative disease pri- that CpG methylation of CTCF binding sites could further desta-
marily affects the cerebral cortex and the striatum. Initial physical bilize triplet repeat expansion (Libby et al., 2008), underpinning
symptoms are chorea, rigidity, and dystonia, and become more the role of DNA methylation in the regulation of neurological
apparent as the disorder progresses. Cognitive abilities become diseases. The HD-associated modification of BDNF gene expres-
gradually impaired, finally leading to dementia (Babenko et al., sion was found, in the hippocampus of female and male HD
2012). mice independent of methylation increases in the gene sequence,
HD is caused by the expansion of CAG triplet repeats in the while there existed a pattern of sex-specific differences in the lev-
HTT gene, which encodes an expanded polyglutamine (polyQ) els of methylation at individual CpG sites, suggesting that such
stretch in the huntingtin (HTT) protein. Normal HTT genes differences might explain the differential regulation of BDNF
contain CAG repeats no more than 35, and are not associated expression in the male and female brains (Zajac et al., 2010). Since
with the disorder. Incomplete penetrance happens with 36–40 it has been reported that the loss of BDNF gene transcription is
repeats. However, when these repeats reach 41 or more, the dis- likely a central factor to the progressive pathology of HD, DNA
ease becomes completely penetrant. The number CAG repeats methylation might be the explanation of such loss, which, how-
accounts for ∼60% of the variation in age of onset, and the rest ever, needs further confirmation. Moreover, extensive changes in
can be explained by modifying genes and environment (Walker, DNA methylation were reported to be linked to expression of
2007).These expanded polyQ sequences in the HTT protein pro- mutant huntingtin gene, revealing the potential effects of DNA
duce aggregates that form intracellular inclusions, leading to methylation alterations on neurogenesis and cognitive decline in
neural loss, particularly in the caudate nucleus (Rubinsztein and patients with HD (Ng et al., 2013).
Carmichael, 2004). Besides, a recent study focused on adenosine A2A receptor
Most studies aimed to find a clear correlation between HD (A2A R), a G-protein-coupled receptor, the expression levels of
and DNA methylation focus on two specific subjects: HTT gene which are sharply reduced in HD (Villar-Menendez et al., 2013).
and triplet repeat expansions. In addition to the genetic fac- The study found increased 5mC levels and reduced 5hmC levels in
tors, environment also plays a vital role in this DNA methylation 5 UTR region of A2A R gene from HD patients compared to age-
-associated mechanism. matched controls, suggesting an involvement of an altered methy-
lation pattern of A2A R gene in HD pathology. Moreover, instead
GENETIC FACTORS, DNA METHYLATION, AND HD of methylated cytosine, a HPLC-based method also detected lev-
Researches on DNA methylation in HD began much earlier than els of 7-methyl guanine in DNA samples both from transgenic
those in PD. In 1988, Wasmuth et al. reported the identification mice and HD patients, revealing aberrant methylation levels in
of a highly polymorphic locus, D4S95, which was demonstrated HD (Thomas et al., 2013), and also widening the range of future
to be tightly linked to the HD gene (Wasmuth et al., 1988). researches on DNA methylation.
Later, methylation was found at the B5 allele of the D4S95 locus,
which was not inherited in a Mendelian fashion, as its appearance DNA METHYLATION AND AMYOTROPHIC LATERAL
depended on the methylation status of the human lymphoblas- SCLEROSIS
toid cells from which DNA samples were obtained (Pritchard INTRODUCTION TO AMYOTROPHIC LATERAL SCLEROSIS
et al., 1989), and such phenomenon disclosed the secret of the ALS is an idiopathic, fatal neurodegenerative disease of the
role of DNA methylation in HD. For the first time, Farrer et al., human motor system. The clinical hallmark of ALS is the presence
in their study of 1764 HD patients explored that DNA methyla- of the lower motor neuron signs in brainstem and spinal cord,
tion might be involved in a genetic imprinting mechanism, and and the upper motor neuron signs in the motor cortex. Loss of

these neurons leads to clinical phenotypes including muscle atro- (Chestnut et al., 2011). In addition, CpG methylation in human
phy, weakness, fasciculation, spasticity, and cognitive dysfunction ATXN2 gene promoter is associated with pathogenic CAG expan-
(Kiernan et al., 2011). Proposed pathogenic mechanisms for ALS sions in spinocerebellar ataxia type 2 (SCA2) cases (Laffita-Mesa
include oxidative stress, glutamate excitotoxicity, impaired axonal et al., 2012). Since such aberrant expansions in ATXN2 were
transport, neurotrophic deprivation, neuroinflammation, apop- shown to contribute to ALS (Lahut et al., 2012), we can expect
tosis, and altered protein turnover, etc. Furthermore, influences that there might exist a link between ATXN2 promoter methyla-
from astrocytes and microglia in the motor neuron microenvi- tion and pathogenesis of ALS.
ronment contribute to ALS pathogenesis (de Carvalho and Swash,
2011). ENVIRONMENTAL FACTORS AND DNA METHYLATION IN ALS
ALS is traditionally classified into two categories: familial ALS Environmental exposure to heavy metals has been implicated in
(FALS) and sporadic ALS (SALS) (Robberecht and Philips, 2013). SALS and functionally impaired detoxification of these metals
FALS is predominantly hereditary and then almost always auto- may cause serious susceptibility to the disease. The metalloth-
somal dominant, while X-linked or recessive FALS is rare. Several ionein (MT) is a family of proteins that are involved in primary
genes and their mutations have been found to be associated with detoxification mechanism for heavy metals. As a matter of fact,
ALS. Superoxide dismutase 1 (SOD1) mutations are the cause in no promoter methylation of human MT genes was evident in any
about 20% of FALS. Also, TARDBP, which encodes TAR DNA- SALS or control samples, implying the possibility that methy-
binding protein, and FUS, a RNA- binding protein fused in lation at these gene promoters may not be a common cause of
sarcoma, also contribute to FALS cases. SALS has been associ- SALS (Morahan et al., 2007). However, altered methylation of the
ated with another gene, ELP3, encoding the catalytic subunit of Alsin (ALS2) gene promoter was observed in hippocampal cells of
the histone acetyltransferase (HAT) complex elongator protein individuals with a history of being abused in childhood (Labonte
(Urdinguio et al., 2009). Additionally, ALS2, ATXN2, and some et al., 2012). Interestingly, higher levels of promoter methylation
other genes are also associated with ALS, which we will discuss were correlated with a repression of ALS transcription suggesting
below (Ferraiuolo et al., 2011). a role of DNA methylation in the regulation of ALS gene.
Not unlike those neurodegenerative diseases we described
above, there is a potential point that ALS is also connected to DNA DISCUSSION
methylation through genetic and environmental factors. We find three topics worth discussing: (1) causal relationship
between DNA methylation modification and neurodegenerative
GENETIC FACTORS, DNA METHYLATION, AND ALS diseases, (2) triggers of DNA methylation modification in neu-
An epigenetic analysis of SOD1 and VEGF (which encodes vas- rodegenerative diseases, and (3) perspectives.
cular endothelial growth factor, a signal protein produced by cells In the field of neurodegenerative diseases, although experi-
that stimulates vasculogenesis and angiogenesis) in ALS showed mental evidence revealed correlations between DNA methylation
that the promoter regions of these genes were widely unmethy- and these diseases, two major questions remain unclear. The first
lated in ALS patients, suggesting transcriptional silencing via question is the causal relationship between DNA methylation
DNA methylation is not likely a common mechanism in ALS modifications and neurodegenerative diseases. In other words, do
(Oates and Pamphlett, 2007). DNA methylation modifications precede the appearance of neu-
In contrast, methylation of the human glutamate transporter rodegenerative symptoms? Is there a proved mechanism demon-
EAAT2 gene promoter has been reported to be associated with strating that DNA methylation modifications will finally lead to
the silent state of the human EAAT2 gene. Since the dysfunction neurodegenerative diseases? Another question is: if DNA methy-
of EAAT2 transporter might contribute to the pathogenesis of lation modifications do cause neurodegenerative diseases, what is
ALS (Rothstein et al., 1995), it is meaningful to further test the the trigger of these methylation modifications in neurodegenera-
regulation of EAAT2 transporter via an epigenetic mechanism tive diseases? This is also a crucial question since it may lead us to
including DNA methylation in ALS models. GLT1 is the analog new paths of curing these diseases.
to EAAT2 in rodent astroglial cells, however, hypermethylation
on specific CpG islands of GLT1 promoter was discovered to par- CAUSAL RELATIONSHIP BETWEEN DNA METHYLATION
ticipate in repression of GLT1 promoter activation, whereas this MODIFICATION AND NEURODEGENERATIVE DISEASES
regulation was not involved in astroglial dysfunction of EAAT2 in Alzheimer’s disease
ALS patients (Yang et al., 2010). Studies also found that a group Evidences generally suggested that DNA methylation modifica-
of genes, either unsuspected in SALS or in potential pathways of tion is a cause instead of a consequence of AD, for several events
cell death, revealed changed methylation status in SALS brains related to DNA methylation occur earlier than AD symptoms.
(Morahan et al., 2009). Because of the controversial findings One clue is that the upregulation of plasma homocysteine
above, there are supposed to be more powerful and convincing (HCY), an independent AD risk factor, occurs prior to the
evidence collected to clarify the involvement of DNA methylation pathogenesis of AD (Clarke et al., 1998; Seshadri et al., 2002).
in ALS by regulating the expression of the human EAAT2. As we know, DNA methylation is accomplished by transfer-
In mouse models, the apoptosis process of motor neurons ring a methyl group from SAM to the 5-position of cytosine.
showed alterations in DNMT1, DNMT3a, and 5-methylcytosine, This metabolic pathway belongs to HCY metabolism (one-
which is similar to those in human ALS, indicating that DNMT carbon metabolism). HCY accumulation leads to upregulation
may mediate neuronal cell death through DNA methylation of S-adenosylhomocysteine (SAH) levels due to the reversibility

of the reaction. To make the reaction proceed in the hydrolytic and Aβ production, in which these two phenomena reinforce each
direction, HCY and Ado have to be efficiently removed (Fuso other and cause AD eventually. This point is interesting, however,
et al., 2005) (Figure 1). SAH, a strong DNA methyltransferase most other studies of this kind showed the opposite result. For
inhibitor, strengthens DNA hypomethylation. Thus, a regula- instance, a recent study showed that amyloid production was not
tion of metabolism through either remethylation or transsulfu- responsible for PS1 demethylation in the brain of TgCRND8 mice
ration pathways may result in hyperhomocysteinemia, decrease (carrying a double-mutated human APP transgene) (Fuso et al.,
of SAM/SAH ratio (also called methylation potential, MP), and 2012a). Therefore, such results need to be further analyzed.
change of GSH levels, suggesting that hypomethylation is a mech-
anism through which HCY is related to vascular disease and Parkinson’s disease, Huntington’s disease, and amyotrophic lateral
AD. Additionally, oxidative stress was shown to promote the sclerosis
production of HCY’s oxidized derivatives, such as homocysteic Similar to AD, the other three major neurodegenerative diseases,
acid and homocysteine sulfinic acid. These compounds inter- i.e., PD, HD, and ALS, are also closely related to DNA methylation
act with glutamate receptors thus increasing intracellular free of several critical genetic loci. While these loci have been exten-
radicals (Fuso and Scarpa, 2011). Following this trail, a series sively studied, some findings seem to disagree with others. In the
of studies demonstrated PS1 gene promoter hypomethylation case of PD, α-synuclein gene is the research spot of interest. There
in cell and mouse models under alterative HCY case (Scarpa have been a series of studies of human PD brain cell samples that
et al., 2003; Fuso et al., 2005, 2007, 2008). These cases are often tested the DNA methylation level of the promoter and intron 1
accomplished by deficiency of vitamin B6, vitamin B12 and of α-synuclein gene and found a different methylation level com-
folate during cell culture and mouse feeding. Moreover, in SK- pared to normal controls (Jowaed et al., 2010; Matsumoto et al.,
N-BE neuroblastoma cells and TgCRND8 mice, such a trend 2010; de Boni et al., 2011). These findings all support the idea
is found to be reverted when SAM was intentionally added to that DNA methylation is involved in PD. However, some other
the culture or diet (Fuso et al., 2011b). Cognitive experiments results are not so positive as they found, while examining blood
in mice and detection of Aβ formation confirmed these results cell samples of PD patients, that α-synuclein expression was not
(Fuso et al., 2012b). It has also been shown that the activi- changed (Richter et al., 2012), or its expression changed indepen-
ties of DNA methyltransferases (DNMT1, DNMT3A, DNMT3B) dent of DNA methylation modification (Voutsinas et al., 2010).
and demethylase (MBD2) are modulated by HCY metabolism in This seems a little controversial, but if we take a closer look at
AD cells and mouse models. Elevated HCY levels decreased the these results against the involvement of DNA methylation in PD,
activity of DNA methylase and the activity of DNA demethy- we can find that these examinations taken with blood cell samples
lase was increased (Fuso et al., 2011a). Since the elevation in are much less convincing than those taken with brain cell samples
the homocysteine level preceded the onset of dementia, stud- in that α-synuclein is widely believed to mainly be localized and
ies from this area implies that global DNA hypomethylation is a functional in mammalian brain neurons (Mclean et al., 2000; Yu
cause of AD. et al., 2007). Other genetic loci with issues are parkin and UCHL1
DNA methylation regulation in aging offers another clue to the genes, which also play important roles in PD pathology, however,
causal relationship. Aging is generally considered to be one of the due to lack of enough evidence so far, we still cannot determine
most salient risk factors for AD, and a strong correlation between whether these loci are affected by DNA methylation or not.
DNA methylation regulation and aging was demonstrated in In the case of HD and ALS, the studies were merely focused on
brain and blood samples (Horvath et al., 2012). Decrement the rough relationship between these diseases and DNA methy-
of S100A2 and increment in SORBS3 CpG methylation in the lation. Although, of course, there are some genetic loci that also
human cerebral cortex during aging was reported, and an accel- have been examined in those researches such as CTCF, BDNF, and
eration of this trend was shown in AD patients (Siegmund et al., ATXN, we can barely come to any specific conclusion because of
2007). Another study including 24 LOAD brains and 10 matched the poor quantity of scientific evidence.
controls revealed epigenetic variability of genes related to AD
among all individuals, and AD patients’ epigenetic distance from TRIGGERS OF DNA METHYLATION MODIFICATIONS IN
the norm was observed to increase progressively with age. It was NEURODEGENERATIVE DISEASES
suggested that epigenetic modifications may merely result in a Alzheimer’s disease
range of interindividual variance until a threshold of epigenetic Knowing that DNA methylation changes do interact with AD and
deregulation is reached. After this point, the brain starts to mal- usually serve as causes, one may seek the origin of these changes
function and AD symptoms occur. Based on this view, LOAD may in DNA methylation patterns. Such pursuit is worthwhile since
represent an extreme form of normal aging (Wang et al., 2008). To it may finally guide us to a new path for treating AD. We divide
sum up, these studies indicated that methylation changes are parts possible causes of DNA methylation regulation in AD into four
of aging, and some of them may result in AD. aspects: aging, B vitamin deficiency, oxidative stress, and heavy
It is noteworthy that there are results from another side. In metal exposure.
a murine cerebral endothelial cells model, it was shown that
Aβ reduces global DNA methylation whilst increasing NEP’s Aging factors. As we mentioned above, aging is a widely-accepted
DNA methylation level and further suppressing NEP’s expres- risk factor of AD, and some reports regarded methylation change
sion in mRNA and protein levels (Chen et al., 2009). This finding related to AD as an acceleration of aging (Siegmund et al., 2007)
suggested a vicious cycle formed by DNA methylation alteration or a specialized case of aging (Wang et al., 2008). These studies

provide a chain of causation from aging to DNA methylation not have pathological results until later in life, was proposed to
deregulation and then to AD. explain these phenomena (Lahiri et al., 2008; Lahiri and Maloney,
2012).
B vitamin deficiency. As we know, DNA methylation is accom-
plished by transferring a methyl group from SAM to the Parkinson’s disease, Huntington’s disease, and amyotrophic lateral
5-position of cytosine and this metabolic pathway belongs to sclerosis
HCY metabolism (one-carbon metabolism). Folate, vitamin B6 Compared to AD, the studies are relatively insufficient about the
and vitamin B12 are crucial for this metabolic cycle since N5 - causal relationship between DNA methylation and other three
methyl-tetrahydrofolate (N5 -methyl-THF, a folate derivative) neurodegenerative diseases as well as the causes of DNA methyla-
donates a methyl group to HCY that then transforms to methion- tion in these diseases. Despite paucity of evidences, a few studies
ine while vitamin B6 and vitamin B12 are involved in methylation showed that environmental factors such as exposure to toxicity
catalysis. Therefore, the deficiency of vitamin B may block the like paraquat and previous physical and mental experiences like a
regular DNA methylation metabolic cycle. This indication is sup- history of being abused in childhood, are related to DNA methy-
ported by experimental evidence in rats (Miller et al., 1994), and B lation in these diseases. However, data we can search so far are so
vitamin deficiency is commonly used as a method to create DNA rough and random findings that no reliable conclusion but sim-
methylation metabolism disorder in current studies (Fuso et al., ply assumptions can be made from them. Therefore, we can see a
2005, 2011b; Chen et al., 2009). In addition to those hypermethy- promising field of interest waiting for further solid research find-
lation and hypomethylation patterns we mentioned above, it was ings to confirm the hypothesis that similar to AD, there is also a
demonstrated that SAH increased DNA damage in BV-2 cells pos- causal relationship between DNA methylation and the other three
sibly by increasing Aβ formation that led to increased formation neurodegenerative diseases (PD, HD, and ALS).
of ROS. Furthermore, the DNA damage was reinforced by SAH
through inhibition of DNMT1 activity and hypomethylation of PERSPECTIVES
OGG1 gene promoter in microglial BV-2 cells (Lin et al., 2011). Expanding rapidly as it is, the field of DNA methylation and neu-
Moreover, HCY inhibits the dimerization of ApoE3 and rodegenerative diseases is facing three main challenges for further
reduces ApoE3-mediated high-density lipoprotein (HDL) gener- progress.
ation (Minagawa et al., 2010). It was shown that HDL apolipopro- First of all, DNA methylation is an emerging field with many
teins can significantly enhance the degradation of soluble Aβ unclear issues. For instance, one may expect that the hyperme-
within microglia, and such degradation was facilitated by the lip- thylation will result in the repression of a gene, however, some
idation of ApoE (Jiang et al., 2008). HCY was reported to impair opposite findings have been reported, such as the coexistence of
ApoE3 dimerization and ApoE3’s ability of generating HDL by overexpression and DNA methylation of the p16INK4a gene (Kim
binding to cysteine residues of ApoE3. Therefore, hyperhomocys- and Sharpless, 2006). Without an accurate comprehension of the
teinemia may promote the pathogenesis of AD (Minagawa et al., relationship between DNA methylation and the regulation of gene
2010). expression, much experimental evidence linking DNA methy-
lation and neurodegenerative diseases may have been misinter-
Oxidative stress. Causing the imbalance between DNA methy- preted or missed. In addition, 5hmC, which used to be regarded as
lation and demethylation, oxidative stress is also known as an only an intermediate in DNA demethylation, was recently found
environmental factor interacting with DNA methylation and AD. to increase with age in the absence of 5mC changes and thus may
Study in SH-SY5Y cells revealed that treatment with H2 O2 may serve as an epigenetic factor of AD (Chen et al., 2012). With the
activate a DNMT inhibitor and result in the upregulation of APP majority of current studies concentrated on normal CpG methy-
and BACE1 through transcription activator-vB, leading to the lation, we cannot ignore that non-CpG methylation and 5hmC
upregulation of Aβ production (Gu et al., 2013). also play an important role in DNA methylation. Since it has been
suggested that non-CpG methylation and 5hmC are dominant
Heavy metal exposure. Infant exposure to lead (Pb) was reported in mammalian brain development (Lister et al., 2013), and since
as another environmental factor contributing to AD through 5hmC is implicated in aging and AD (van den Hove et al., 2012),
DNA methylation regulation. Developmental exposure of rodents further studies should include these specific cases in order to give
to the heavy metal lead has been shown to increase APP and us a better understanding of how the DNA methylation is exactly
Aβ in aging brain (Basha et al., 2005). Study in aged monkeys related to the pathologies of neurodegenerative diseases.
showed that the group that was fed with Pb in their early life has Another challenge is that DNA methylation patterns vary
a lower DNMT activity. The downregulation of DNMT activity in different cells as well as different brain regions. Study in
thus results in the hypomethylation of several genes involved in human frontal cortex showed that neurons and glial cells do not
Aβ formation such as APP and BACE, and causes the upregu- share a same DNA methylation profile, nor do different neurons
lation of APP, BACE, and Sp1 in turn, which finally results in (Iwamoto et al., 2011). Since each type of cells in nervous system
Aβ formation and AD (Wu et al., 2008). These finding are con- plays a distinct role, research ignoring variation among cells may
firmed by a genome-wide study on mice (Bihaqi et al., 2011) and not be able to provide sufficient evidence for this topic. Moreover,
an in vitro study (Bihaqi and Zawia, 2012). A latent early-life different regions of the brain, which have various importance
associated regulation (LEARn) model, which claims that envi- in neurodegenerative diseases, were shown to express genes dif-
ronmental agents perturb gene regulation at early stage but do ferently (Twine et al., 2011). Therefore, conclusions cannot be

Table 1 | Altered DNA methylation profiles observed in neurodegenerative diseases.
Disease Category of genes Specific genetic loci DNA methylation regulation Possible effect
AD Aβ-related genes APP Hypomethylation or none Over expression of Aβ

PSEN1 Hypomethylation
BACE1 Hypomethylation
APBA2 Hypermethylation
Aβ-degradation-related genes NEP Hypermethylation Aβ accumulation
SORL1 Hypermethylation
Tau-related genes GSK3β Hypomethylation Disorder of tau
Genes involved in metabolic OTC Hypomethylation Metabolic dysfunction
pathways
rDNA rDNA Hypermethylation Ribosomal deficits
Others Circadian gene (PER1 Hypermethylation Behavioral and psychological symptoms
and CRY1)
LINE-1 Hypermethylation Unknown
NGB Unknown AD severity regulation
Telomere Hypomethylation Cell entering into a senescent state
COX-2 Hypomethylation Brain AA cascade enzymes upregulation
BDNF Hypermethylation Loss of neurotrophic factors
CREB Hypermethylation Exacerbation of BDNF reduction
SYP Hypermethylation Loss of synaptic proteins
NF-kB Hypomethylation Neuroinflammation
S100A2 Hypomethylation Protein accumulation
SORBS3 Hypermethylation Cell adhesion dysfunction
PD SNCA SNCA (intron1 and Hypermethylation Decreased expression of SNCA

promoter)
Hypomethylation Overexpression of SNCA
Inflammatory cytokines TNF-α Hypomethylation Increased risk of apoptosis in
dopaminergic neurons
Clock genes CRY1 Devoid of methylation Disorder of circadian rhythms
NPAS2
Telomere Subtelomeric region Constant methylation Telomere shortening
Other genes PARK16/1q32 Methylation alteration PD risk
GPNMB
STX1B
Cytochrome P45 2E1 Hypomethylation Increased PD susceptibility
HD HTT gene Promoter region of HTT Extensive methylation alteration Neurogenesis and cognition
gene
Oligodeoxyribonucleotides Cytidine Hypermethylation Expansion of triplet repeat sequences
Genome Genome-wide Hypomethylation Instability of CTG/CAG trinucleotide
repeats
CTCF CTCF binding sites CpG methylation
BDNF Promoter region of Gender-specific methylation Differential regulation of BDNF gene
BDNF expression
ALS SOD1 Promoter regions of Hypomethylation No transcriptional silencing

VEGF SOD1 and VEGF
EAAT2 Promoter regions of Hypermethylation Functional loss of EAAT2 transporters
EAAT2
GLT1 Promoter region of Hypermethylation
GLT1
ATXN2 Promoter region of Hypermethylation Pathogenic CAG expansions
ATXN2

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We thank Dr. Immo Scheffler (Section of Molecular Biology, hydroxymethylcytosine in the mouse hippocampus. Restor. Neurol. Neurosci. 30,
University of California San Diego, La Jolla, California, United 237–245. doi: 10.3233/RNN-2012-110223
States of America) for extensive language editing of this Chen, K. L., Wang, S. S., Yang, Y. Y., Yuan, R. Y., Chen, R. M., and Hu, C. J. (2009).
The epigenetic effects of amyloid-beta(1-40) on global DNA and neprilysin
manuscript. This work was supported by National Natural genes in murine cerebral endothelial cells. Biochem. Biophys. Res. Commun. 378,
Science Foundation of China (NSFC 81171206). 57–61. doi: 10.1016/j.bbrc.2008.10.173
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Yu, J., Tao, Q., Cheung, K. F., Jin, H., Poon, F. F., Wang, X., et al. (2008). Epigenetic Conflict of Interest Statement: The authors declare that the research was con-
identification of ubiquitin carboxyl-terminal hydrolase L1 as a functional tumor ducted in the absence of any commercial or financial relationships that could be
suppressor and biomarker for hepatocellular carcinoma and other digestive construed as a potential conflict of interest.
tumors. Hepatology 48, 508–518. doi: 10.1002/hep.22343
Yu, S., Li, X., Liu, G., Han, J., Zhang, C., Li, Y., et al. (2007). Extensive Received: 08 August 2013; accepted: 17 November 2013; published online: 05 December
nuclear localization of alpha-synuclein in normal rat brain neurons 2013.
revealed by a novel monoclonal antibody. Neuroscience 145, 539–555. doi: Citation: Lu H, Liu X, Deng Y and Qing H (2013) DNA methylation, a hand
10.1016/j.neuroscience.2006.12.028 behind neurodegenerative diseases. Front. Aging Neurosci. 5:85. doi: 10.3389/fnagi.
Zajac, M. S., Pang, T. Y., Wong, N., Weinrich, B., Leang, L. S., Craig, J. M., et al. 2013.00085
(2010). Wheel running and environmental enrichment differentially modify This article was submitted to the journal Frontiers in Aging Neuroscience.
exon-specific BDNF expression in the hippocampus of wild-type and pre-motor Copyright © 2013 Lu, Liu, Deng and Qing. This is an open-access article distributed
symptomatic male and female Huntington’s disease mice. Hippocampus 20, under the terms of the Creative Commons Attribution License (CC BY). The use, dis-
621–636. doi: 10.1002/hipo.20658 tribution or reproduction in other forums is permitted, provided the original author(s)
Zhang, W., Tian, Z., Sha, S., Cheng, L. Y. L., Philipsen, S., and Tan-Un, K.-C. (2011). or licensor are credited and that the original publication in this journal is cited, in
Functional and sequence analysis of human neuroglobin gene promoter region. accordance with accepted academic practice. No use, distribution or reproduction is
BBA 1809, 236–244. doi: 10.1016/j.bbagrm.2011.02.003 permitted which does not comply with these terms.

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published: 05 December 2013

DNA methylation, a hand behind neurodegenerative

INTRODUCTION made in the study of DNA methylation in four major neurode-

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Table 1 | Altered DNA methylation profiles observed in neurodegenerative diseases.

AD Aβ-related genes APP Hypomethylation or none Over expression of Aβ

PD SNCA SNCA (intron1 and Hypermethylation Decreased expression of SNCA

ALS SOD1 Promoter regions of Hypomethylation No transcriptional silencing

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