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Publicly Available Published by De Gruyter November 21, 2012

The ‘golden age’ of DNA methylation in neurodegenerative diseases

  • Andrea Fuso

    Andrea Fuso, PhD, is Assistant Professor at Sapienza University of Rome within the Department of Psychology – Section of Neuroscience. He achieved his graduation in Biological Sciences at Sapienza University in 1997 and his PhD in Enzymology in 2001. He teaches at the post-graduation School of Clinical Pathology and at the School of Psychology at Sapienza University of Rome. His main research interest focuses on the one-carbon metabolism, with particular attention to DNA methylation mechanisms and their relationship with gene expression. In the field of basic science, he is interested in the dynamics of DNA methylation/demethylation patterns and the study of non-CpG methylation. As applicative fields, he studies the role of epigenetics, nutrition and one-carbon metabolism on Late Onset Alzheimer’s Disease and neurodegenerative diseases as well as in Rett syndrome, autism, neurodevelopment and muscle differentiation.

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DNA methylation reactions are regulated, in the first instance, by enzymes and the intermediates that constitute the ‘so called’ one-carbon metabolism. This is a complex biochemical pathway, also known as the homocysteine cycle, regulated by the presence of B vitamins (folate, B6, B12) and choline, among other metabolites. One of the intermediates of this metabolism is S-adenosylmethionine, which represent the methyl donor in all the DNA methyltransferase reactions in eukaryotes. The one-carbon metabolism therefore produces the substrate necessary for the transferring of a methyl group on the cytosine residues of DNA; S-adenosylmethionine also regulates the activity of the enzymes that catalyze this reaction, namely the DNA methyltransferases (DNMTs). Alterations of this metabolic cycle can therefore be responsible for aberrant DNA methylation processes possibly leading to several human diseases. As a matter of fact, increasing evidences indicate that a number of human diseases with multifactorial origin may have an epigenetic basis. This is also due to the great technical advances in the field of epigenetic research. Among the human diseases associated with epigenetic factors, aging-related and neurodegenerative diseases are probably the object of most intense research. This review will present the main evidences linking several human diseases to DNA methylation, with particular focus on neurodegenerative diseases, together with a short description of the state-of-the-art of methylation assays.


There has been a huge increase in research on epigenetics in the last 10 years. A simple PubMed search for the term ‘epigenetic’ shows about 300 papers in the year 2000; this number rises to more than 3500 papers in 2012 (not yet concluded). While considering these data, one caveat should be taken into account: ‘epigenetics’ has become a voguish word; therefore, in the count of the number of research articles and papers claiming to study epigenetic modifications we found several works in which the epigenetics aspects are just touched upon (or even just evoked) or in which biological regulations not strictly definable as ‘epigenetic’ are studied. In this sense, a revision of the significance and definition of ‘epigenetics’ is advisable.

The reasons for the incredible increase of the interest in epigenetic mechanisms due to two main events: 1) the evolution of our technical skills and protocols to study the epigenetic signatures; and 2) the idea that epigenetic modifications are involved in many different human diseases.

The history of the epigenetics has been characterized by three ages. The term ‘epigenetics’ was conceived in 1942, when the exact nature and functions of genes were not yet known [1]. After a quiet period we observed the development of this discipline in the 1980s, when it was demonstrated that epigenetic mechanisms (namely DNA methylation) were involved in the regulation of the developmental and differentiation pathways in an organism. DNA methylation was related to embryonic development [2, 3], cell differentiation [4], X chromosome inactivation [5] and terminal differentiation [6]. A decade later, epigenetics encountered its middle age and new fuel when it was demonstrated that it is associated with different cancers [7] and possibly other diseases [8]. At the beginning of the new millennium, however, only three diseases where recognized as directly dependent on epigenetic causes: Fragile X syndrome [9], Rett syndrome [10] and ICF syndrome [11]. Then another quiet period occurred, due in a large part to the contrasting results derived from the studies on cancer; as a matter of fact, the evidence that both hyper- and hypomethylation could be associated to cancer risk and onset and could sometimes be concomitant in the same organism [12–14] instilled some doubt and was the cause of the frequently heard opinion that DNA methylation was ‘some kind of a confused and unclear modification’. However, this negative idea has been revised as the ability to perform more accurate epigenetic analyses enables better clarification of the functional role of hyper- and hypomethylation in different DNA domains [15–17]. Therefore, the technical progresses and the concomitant reinforcement of the knowledge that epigenetics is probably involved in several human diseases [18, 19] and acts as a mediator of environmental stimuli [20] is focusing renewed and increased interest in the study of epigenetic modifications. Since many of the pathologies associated with epigenetic modifications are in the area of the neurodegenerative diseases [21], we can define this as the ‘golden age’ of epigenetics.

Technical advances in epigenetic studies

In the recent years, progress in the biochemical techniques used for the study of the epigenetic modifications has been impressive. This is particularly true for the study of DNA methylation.

Table 1

Overview of bisulfite-based techniques for the study of DNA methylation.

Table 1 Overview of bisulfite-based techniques for the study of DNA methylation.

DNA methylation was originally studied at the genomic level, by analyzing total 5-methylcytosine (5mC) in DNA by chemical hydrolysis and chromatographic revelations [22, 23]. More recently, the development of the capillary electrophoresis made this assay faster, cheaper and more sensitive; however, although it allows the accurate quantification of total DNA methylation, this technique has some limitations due to the necessity of the large amount of starting material and expensive equipment. Moreover, it allows only total methylation to be assessed, without any sequence information. Today, three different strategies are used, often in combination, resulting in a large panel of assays oriented toward the study of different aspects of DNA methylation and allowing the determination of sequence-specific methylation pattern: endonuclease digestion with methylation-sensitive enzymes, chemical modification by bisulfite and purification of methylated genome fractions by methylation-specific antibodies.

Among these, the use of methylation-sensitive (and insensitive) enzymes is the first approach used for studying the methylation pattern of individual and specific sequences. The major limits of this approach are related to the possibility of incomplete DNA digestion and to the limitation of the cleavage sites recognized by methylation-sensitive endonucleases. Once the DNA is digested with a methylation-sensitive restriction enzyme, whose recognition site is located inside the sequence of interest, the methylation state can be either determined by Southern blot, using a specific probe overlapping the target site (this approach, although reliable, is awkward and requires a considerable amount of DNA) or by PCR, using specific primers flanking the target site (this strategy requires a smaller amount of DNA and is more sensitive, but it is more prone to false-positive results due to incomplete digestion) [24]. Although today, bisulphite-based approaches represent the state-of-the-art for the study of sequence-specific DNA methylation, methylation-sensitive enzymes found new applications in genome-wide methylation analyses.

Sodium bisulfite selectively reacts with unmethylated cytosines converting them to uracils leaving the methylated cytosines unmodified [25]. This reaction is highly single-strand dependent and cannot be performed on double-strand DNA, therefore requiring initial DNA denaturation. This is a crucial step of the method, since partial denaturation can cause the incomplete transformation of certain unmethylated cytosines and, consequently, can create artifacts such as false positives. The reaction is the basis for differentiating methylated DNA from unmethylated DNA but it needs to be combined with other methods to assess the methylation state of a given DNA sequence. In general, bisulphite-associated strategies require PCR amplification of the transformed DNA (which incorporates T for U) and the design of target specific methylation-dependent primers. However, the method of analysis of the amplified PCR products can vary depending on the degree of specificity and detail of methylation required, giving rise to a large assortment of techniques:

  • The COmbined Bisulphite Restriction Analysis (COBRA) method is based on the fact that DNA conversion by bisulphite can create new restriction enzyme sites or modify preexisting sites on a methylation-dependent basis [26]. Therefore, some endonucleases are able to bisulfite methylated and unmethylated moieties when digesting PCR products of bisulfite-treated DNA. This approach provides semi-quantitative data since the methylation level is correlated with the relative amount of digested and undigested PCR products; digested products can be quantified by hybridization with labeled oligonucleotides and phosphoimager detection. As for each technique based on the use of restriction endonucleases, this method is limited to the restriction enzyme recognition site and can be affected by incomplete bisulphite conversion and/or partial DNA digestion.

  • A mass spectrometric sensitive approach has also been developed that is appropriate for the detection of methylation, for the discrimination between methylated and non-methylated samples, and for the identification of differentially methylated sites through quantitative analysis of methylation [27]. The method takes advantage of a T7-promoter-tagged PCR amplification of bisulphite-converted DNA, followed by the generation of a single-stranded RNA molecule and subsequent base-specific cleavage (3′ to either rUTP or rCTP) by RNase A. The mixture of cleavage products differing in length and mass are analyzed by MALDI-TOF-mass spectrometry.

  • A method to differentiate converted from unconverted bisulfite-treated DNA is based on the use of the high resolution melting analysis (HRM), a real-time PCR-based technique initially designed to distinguish SNPs [28]. PCR products are directly analyzed by temperature ramping and resulting liberation of the intercalating fluorescent dye during melting. The methylation degree, as represented by the C-to-T content in the amplicon, determines the rapidity of melting and the consequent release of the dye. This method allows direct quantitation in a single-tube assay, but only assesses methylation in the amplified region as a whole and cannot distinguish specific CpG sites.

  • Bisulphite-modified DNA can also be directly analyzed by methylation specific PCR (MSP), which represent the most widely used method to detect CpG-island methylation [29]. This approach is simple, sensitive (to 0.1% methylated alleles of a given CpG-rich locus), rapid and requires small amounts of DNA, allowing the study of samples such as paraffin-embedded or microdissected tissues. It is based on the design of primers containing CpG dinucleotides that anneal specifically with either the transformed (unmethylated) or unmodified (methylated) molecules of the bisulfite-treated DNA, which is the critical and complex step of the procedure. It is important to consider that bisulfite-converted DNA is not self-complementary, so that primers that are designed to amplify the top strand of a particular sequence will be different from those that are designed to amplify the bottom strand.

  • A quantitative version of MSP is MethyLight, which uses fluorescence-based real-time PCR and requires no further manipulation after the PCR step [30]. This method specifically employs TaqMan technology, based on the design of three oligonucleotides: specific forward and reverse PCR primers and the fluorogenic probe hybridization, which offers the opportunity for several detection strategies so that the sequence discrimination can occur at the level of the PCR amplification process and/or at the level of the fluorogenic probe hybridization. Fluorescence detection results in a large increase of the sensitivity since it detects a single methylated allele in 105 unmethylated alleles.

Most of the previous techniques can be combined with genomic-scale approaches such as fingerprinting or microarrays to allow the assessment of multiple sequences or the screening of novel markers.

The restriction landmark genomic scanning (RLGS) was one of the earliest approaches used for genome-wide analyses [31]. In this assay, genomic DNA is digested with a rare sensitive-methylation restriction enzyme, radioactively end-labeled at the cleavage sites and size-fractionated in one dimension. Then the fractionated DNA is further digested with a more frequently occurring endonuclease and resolved in the second dimension. The method gives rise to a two-dimensional profile with thousands of spots representing different unmethylated sequences, whose location and intensity indicate its locus and the copy number of the corresponding restriction site, respectively. Profiles of different samples can be compared to detect methylation differences and the spots of interest can be isolated, cloned and identified.

Another genome-wide method based on the use of sensitive and insensitive-methylation endonucleases is the methylated CpG-island amplification (MCA) [32]. DNA is digested with the sensitive enzyme SmaI (CCCGGG), which cuts unmethylated sites leaving blunt ends, and is followed by digestion with the isoschyzomer XmaI, which cleaves the remaining methylated sites but leaves overhanging ends to which specific adaptors are ligated. The last step is the PCR amplification with primers that anneal the XmaI adaptor sequence. Since about 70%–80% CpG islands contain two close SmaI/XmaI sites, the amplified products are enriched in this kind of sequence. In MCA, differentially methylated sequences are identified by representational difference analysis (RDA), which is a subtraction technique, but the identification of the hypermethylated sequences is a laborious task, although more recently it has been coupled to microarrays.

Amplification of intermethylated sites (AIMS) is another method based on the MCA approach but in this case the ligated sequences are amplified by PCR using adaptor-specific primers extended at the 3′ end to reduce the complexity of the sample [33]. PCR products are resolved in denaturing polyacrylamide-sequencing gels generating readable fingerprints that consist of multiple anonymous bands that represent the methylome of the cell. Although the isolation and identification of the sequences with differential methylation is arduous, it is a suitable approach for the comparison of a large series of samples and, when coupled with microarrays, genome-wide results may be obtained.

Multiple methods for the study of DNA methylation at the genome scale involve the use of microarrays. In recent years many high-quality commercial arrays have been made widely available, these include lithographic (Affymetrix), adaptive lithographic (NimbleGen), inkjet (Agilent) and bead arrays (Illumina). In these assays, arrays containing a number of known CpG island sequences are hybridized with a sample enriched in CpG islands obtained by the digestion of genomic DNA methylation-sensitive endonucleases. It should be noted that its specificity relies on the efficient digestion of genomic DNA, so a partial digestion could lead to false-positive results.

Microarrays for the analysis of bisulfite-treated DNA have also been designed. In this case, pairs of oligonucleotides with sequences annealing either the unmethylated or the methylated version of the DNA regions of interest are immobilized as different spots on one array, and each probe can interrogate one or more CpGs, lending this system’s remarkable flexibility. Samples being hybridized are prepared by PCR amplification of a bisulfite-modified DNA using primers that do not contain CpG sites so that methylated and unmethylated regions are amplified equally. The ratio of methylated and unmethylated DNA in the sample is determined by comparing the hybridization to methylated vs. unmethylated oligonucleotides. Employing this approach, any region of the genome can be analyzed, but each region must be amplified individually by PCR [34–37].

More recently, techniques based on chromatin immunoprecipitation using ChIP-on-chip approach have provided new insights in DNA methylation profiling [38]. For example, DNA immunoprecipitated with an antibody that recognizes CpG-methyl-binding domains (MBDs), which have a high affinity for binding methylated CpG sites, has been hybridized on CpG islands microarrays.

A new methylated DNA purification technology based on the direct immunoprecipitation of methylated DNA, called methyl-DNA immunoprecipitation (MeDIP), has been developed. This assay uses a monoclonal antibody that recognizes 5-methylcitosines allowing purification of methylated DNA, but the enrichment is biased towards CpG-rich regions so that its sensitivity is very low outside CpG islands [39].

Finally, recent advances in comparative genomic hybridization (CGH) and quantitative analysis of methylated alleles (QAMA) are further expanding our ability to study epigenetic alterations in disease [9].

‘DNA methylation-based’ diseases

As mentioned above, in the early 2000 only three human diseases had a recognized epigenetic cause: Fragile X, ICF and Rett syndromes; in all these cases the epigenetic modification responsible for the disease was DNA methylation. The first to be identified was the Fragile X syndrome [40]. This form of mental retardation is mainly caused by a CGG triplet repeats expansion in the 5′-untranslated region of the Fragile X mental retardation-1 (FMR1) gene. In subjects affected by Fragile X syndrome, the CGG repeats are hypermethylated causing FMR1 gene repression. ICF and Rett syndromes are characterized by mutations in genes codifying for proteins involved in the regulation of the DNA methylation homeostasis [10, 11]. Immunodeficiency, Centromere instability and Facial abnormalities (ICF) syndrome is caused by mutations on the gene for the Dnmt3b protein, which is a de novo DNA methylase. Rett syndrome is a neurological disease associated with severe dysfunctions and growth retardation and is caused by mutations in the MeCP2 X-associated gene (codifying for a methyl-binding protein).

Today we know that DNA methylation alterations can contribute to a large number of different diseases as a result of different mechanisms. For example, many of the diseases associated with aberrant DNA methylation show methylation-based imprinting alterations; these include Angelman syndrome, Silver-Russell syndrome, Prader-Willi syndrome and Beckwith-Wiedemann syndrome, cancer, diabetes, schizophrenia and autism [41]. As for the cancer, DNA hypermethylation is associated with silencing of tumor suppressor genes whereas hypomethylation is associated with oncogene activation and with chromosome instability. An increasing body of evidence also indicates that many aging-related diseases have an epigenetic basis or at least an epigenetic component; among these, besides the above cited diabetes and cancer, we can found several neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease and many others [42], as discussed in the next paragraph. Aberrant DNA methylation could also be induced independently on gene imprinting, as a consequence of environmental factors as physical and mental stresses, imbalance of nutrients, or contact with pollutants and chemicals entities [43–47].

Environmental factors and epigenetic changes are particularly associated with autoimmune disorders. It is well known that epigenetic modifications are relevant to aging; currently we are exploring their role as important mediators between the environment and the development and progression of numerous autoimmune diseases. For example, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are autoimmune disorders that have frequently been associated with aberrations in epigenetic mechanisms [48]. As a matter of fact, sequence-specific DNA methylation changes have been evidenced in SLE and RA as responsible for the alterations of key genes in immune function.

Strictly linked to the immune systems disorders, allergic disorders appear to be linked to epigenetic changes due to the role of environmental factors in early life [49]. According to emerging theories, in utero exposure to specific factors may be associated with epigenetic aberrations affecting the expression of genes involved in immune programming, thus resulting in the development of allergic disorders in the offspring and, maybe, [50] in future generations. Asthma is a common disorder of this nature and there is some evidence that corticosteroids exert their anti-inflammatory effects in part by inducing acetylation of anti-inflammatory genes [51]. Early intervention into epigenetic-modifying factors, such as maternal diet, may be useful for preventing the onset of these disorders.

Among the different environmental factors affecting the epigenome, nutritional factors seem to play a fundamental role, in particular, in obesity and diabetes. The role of nutritional factors in obesity strongly suggests a role of epigenetic changes mainly involving DNA methylation [52] and early-life environmental factors could be especially important in controlling epigenetic aberrations that may contribute to obesity [53]. Nutritional or lifestyle interventions either during pregnancy or in early-life could impact epigenetic modifications that are highly responsive to environmental stimuli evidencing new strategies to control the obesity ‘epidemic’. Similar to obesity, and in strict correlation with this condition, environmental factors are very relevant in the development of type-2 diabetes. Aging, nutrition and sedentary lifestyle have been associated with epigenetic changes characteristic of type-2 diabetes [54]. DNA methylation have been shown to vary in diabetic vs. non-diabetic subjects, therefore this association strongly stresses for the existence of an epigenetic basis in the pathogenesis of type-2 diabetes [55].

Increasing evidence has shown that epigenetic processes, such as DNA methylation and histone acetylation can play a major role in maintaining and modulating smooth muscle cells (SMCs) and endothelial cells (ECs) [56, 57]. It is known that alteration of SMC and EC proliferation, migration, differentiation and apoptosis is responsible for different cardiovascular diseases such as atherosclerosis, cardomyocite hypertrophy and heart failures. Therefore, epigenetic changes can be considered as directly involved in the onset of this class of diseases; moreover, also in these cases, a major role in modifying epigenetic marks leading to cardiovascular diseases is played by environmental factors, mainly linked to nutrition [58].

A different class of environmental factors potentially responsible for the induction of epigenetic modification is represented by the infections of viral and bacterial origin; even protozoa can induce changes in the epigenetic profile of the host organisms [59]. These infectious agents can induce epigenetic alterations in the host cells leading to different diseases including neoplasia and diseases of the oral cavity [60].

DNA methylation and neurodegeneration

One of the newer and more rapidly expanding applicative areas of epigenetics is related to the role of this class of modifications in neurological disorders or diseases. However, the number of neurodevelopmental disorders that have so far been associated with epigenetic aberrations is very limited. Several neurodevelopmental disorders are due to partial loss-of-function mutations or are mosaics with recessive X-linked mutations. On the contrary, the list of the aging-associated neurodegenerative diseases showing the involvement of aberrant epigenetic processes is very long. This datum counteracts the observation that only a small percentage of neurodegenerative disorders are caused by evident genetic mutations with Mendelian patterns of inheritance; the most widely known are represented by Huntington’s disease (HD; caused by expansion-repeat in the huntingtin gene, HTT), the familial forms of Parkinson’s disease (PD, caused by mutations in different genes as α-synuclein, parkin, PTEN induced putative kinase 1, parkinson protein 7, leucine-rich repeat kinase 2 and glucosidase-ß acid genes) and the familial forms of Alzheimer’s disease (caused by mutations in amyloid precursor protein, presenilin1 and presenilin2 genes) [61]. As a matter of fact, most of the cases of neurodegenerative disease, including mainly AD, PD, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) among others, have their basis in the highly complex and poorly characterized interconnections between genetic and environmental risk factors.

Environmental factors such as diet, nutrients, injuries, physical and cognitive exercise and exposure to chemical agents or heavy metals may be responsible for the epigenetic changes often involved in the onset and progression of neurodegenerative diseases. Association between these environmental factors mediating epigenetic changes has been particularly evidenced in Alzheimer’s disease [47, 62, 63].

Among these environmental factors, one of the most studied aspects is probably related to the role that unbalanced intake of specific nutrients may have on the onset and progression of different diseases through the mediation of epigenetic changes. In particular, the role that B vitamins have in the regulation of one-carbon metabolism and in the alteration of the methylation potential is well known [47]. One-carbon metabolism is indeed regulated by the presence of folate, vitamin B12 and vitamin B6 (among other metabolites) and one major intermediate of this metabolic pathway is the methyl donor molecule S-adenosylmethionine (SAM). SAM acts a donor of methyl groups that can be added by specific methyltransferases to different substrates (lipids, proteins, RNA and DNA). After the transfer of the methyl group, SAM is converted in S-adenosylhomocysteine (SAH); this molecule is also a negative regulator of methyltransferase reactions but it is normally transformed to homocysteine (HCY). Two of the pathways responsible for HCY transformation involve B vitamins: in the remethylation pathway, HCY is remethylated to methionine (the precursor of SAM) in a reaction involving folate and vitamin B12; in the transsulfuration pathway HCY is initially converted to cystathionine (further leading to glutathione synthesis) in a reaction involving vitamin B6. Deficiency of these three B vitamins, caused either by scarce intake or malabsorption, may be reflected in impaired HCY transformation and consequent SAH accumulation, since the equilibrium dynamics of the reaction converting SAH to HCY favors SAH synthesis. Therefore, alteration of the one-carbon metabolism through either remethylation or transsulfuration pathways can lead to hyperhomocysteinemia and decrease of the SAM/SAH ratio [(often indicated as the ‘methylation potential’ (MP)] eventually causing the improvement of the methyltransferase reactions [47]. Thus, impaired DNA methylation can represent the mechanism by which B vitamin deficiency is related to neurodegeneration. It is well known, indeed, that hyperhomocysteinemia and B vitamin deficiency are related to loss of brain volume and to cognitive and memory decline [64, 65] through mechanisms involving the imbalance of both methylation and redox potentials, causing alterations of calcium influx, amyloid and tau protein accumulation, apoptosis, and neuronal death, either directly or by alteration of gene expression [66].

One of the most intriguing (but also complicating) characteristics of the dynamics of epigenetic changes is that they may have originated in the early life of the organism and become manifest in the elderly [67].

As a matter of fact, studies on cognitive disorders are showing accumulating evidence that the onset of a diseased state is dependent on the interaction between the environment and the genes [68] and alterations in the genome-environment interaction may be really important in the pathogenesis of neuropsychiatric and neurodegenerative diseases [69].

Aberrations in DNA methylation leading to neurodegenerative disorders could also be due, as recently demonstrated, to mutations in genes codifying for methylation factors. For example, DNMT1 mutations, causing enzyme loss of function and altered methylation profiles, are responsible for hereditary forms of central and peripheral neurodegenerative disorders such as dementia, sensory neuropathy, hearing loss [70], cerebellar ataxia and narcolepsy [71]. In the first study, mutations were all located within the targeting-sequence domain of DNMT1, in exon 20, causing premature degradation of mutant proteins, reduced enzyme activity and impaired heterochromatin binding leading to global hypomethylation and site-specific hypermethylation. In the second study, mutations were all close within exon 21, suggesting that the distinct location of mutations in this gene is relevant to the differential phenotype.

Experimental evidences in cell culture and animal models also suggest that disturbed expression and altered function of DNA methyltransferases can modulate neurodegeneration. For example, it was demonstrated that overexpression of DNMT3a induces neurodegeneration and apoptosis, whereas DNMT3a depletion, or mutations causing loss of function, and DNMTs inhibitors reduce apoptotic processes in motor neurons [72]. In the same study, corresponding alterations in DNMT1 and DNMT3a and in DNA methylation levels were found in motor neurons isolated from tissues of patients with amyotrophic lateral sclerosis (ALS); these findings allowed correlating DNMTs alterations to ALS and other neurodegenerative processes. Another study demonstrated that DNMT1 knock-out increases expansion repeat instability in human cell culture and causes aberrant DNA methylation and CAG repeats expansion in mice germline at the spinocerebellar ataxia type 1 (SCA1) locus [73].

Today, a number of genes and loci have been identified that show differential or aberrant methylation in several neurodegenerative disorders, particularly in the sporadic forms of these diseases. Some of these genes are specifically associated with one form of disease whereas, others have been shown to contribute to different disorders; furthermore, some neurocognitive disorders were associated with aberrant DNA methylation in different loci [74].

Frataxin (FXN) gene, belongs to the first group: it carries the characteristic GAA repeat mutation responsible for the Friedreich’s ataxia, but it was shown that the expression of this mutant gene is regulated by its methylation pattern in correlation with the age of onset of the syndrome and with the severity of the phenotype [75]. Another gene involved in a form of ataxia, the spinocerebellar ataxia type 2 (SCA2), is the ataxin-2 (ATXN2) gene; the CAG repeat in the mutant gene only partially accounts for the wide range of observed age of onset. It was demonstrated that DNA methylation might regulate the expression of the mutant gene modulating the onset and the severity of the disease [76]. Since this gene is also involved in Parkinson’s disease, amyotrophic lateral sclerosis and frontotemporal lobar degeneration, it is highly probable that at least a part of the epigenetic contribution hypothesized for these diseases can be attributable to the methylation pattern of the ATXN2 gene. The role of DNA methylation in sporadic PD was also evidenced by other studies on SNCA gene. It is well known that mutation and expression levels of this gene are associated with PD [77]; interestingly, SNCA promoter was found to be significantly demethylated in the cortex, substantia nigra and putamen obtained from patients affected by the sporadic form of PD, stressing that DNA hypomethylation could be causative for SNCA overexpression in the disease [78]. It was also shown that the hypomethylation of a specific CpG-rich region was characteristic of specific brain areas from subjects with sporadic PD, pointing to the concept that different brain areas show differential susceptibility to gene-specific methylation in PD and maybe in other neurodegenerative diseases [79]. Finally, a genome-wide association meta-analysis evidenced that other loci associated to PD risk (PARK16, GPNMB, and STX1B) are characterized by differential expression and DNA methylation in cortex and cerebellum [80].

Among the neurodegenerative disorders, Alzheimer’s disease (AD) represents a primary challenge and the main area of research due to the very high incidence and the costs of the sanitary assistance. It also represents a field of intense studies on the possible role of environmental and lifestyle factors and on the epigenetic causes of its variable onset, progression and severity [63].

The complex, non-Mendelian, etiology of AD suggests that epigenetic modifications could be relevant mechanisms mediating AD onset and progression. The development of widescale analysis techniques applied to the study of epigenome revealed that DNA methylation in individuals’ changes over time and also sequence-specific DNA methylation patterns dynamically change during the lifespan and are characteristic and different between different brain areas [81, 82]. It has also been demonstrated that epigenetic changes can contribute to AD onset and course [83, 84] and that specific loci, such as PSEN1, result in demethylation in AD subjects. Although the DNA methylation data in AD subjects needs further confirmation, many preclinical indications stress a central role for methylation, connecting amyloidogenic, fibrillogenic and oxidative pathways in AD. In our laboratory, e.g., we were able to demonstrate the existence of a cascade of causal correlations that, starting from a nutritional intervention, is able to modulate methylation metabolism, alter DNA methylation, modify the expression of PSEN1 gene and finally modulate amyloid processing and deposition [85–87]. In our experiments we treated a transgenic mouse model of AD, the TgCRND8 mice with a diet deficient of vitamin B12, B6 and folate; these vitamins are, as discussed above, fundamental for one-carbon metabolism homeostasis, for the regulation of the methylation potential and for the activity of methyltransferases. As we demonstrated, the environmental stress represented by B vitamins deficiency sequentially resulted in decreased SAM/SAH ratio, impaired methylation potential, DNMTs inhibition and DNA demethylase stimulation, PSEN1 promoter hypomethylation, PSEN1 overexpression, increased amyloid processing and deposition in senile plaques and, finally, cognitive impairment. The supplementation with SAM was, however, able to restore control-like conditions in AD mice or even to partially revert the Alzheimer-like phenotype [47, 85]. Other papers confirmed, directly or indirectly, the role of B vitamins and DNA methylation in the molecular mechanisms related to AD onset and progression [63], although other studies seem to suggest the possibility that changes in DNA methylation could be regulated by amyloid rather than regulate amyloid processing [88, 89]. It appears to show that DNA methylation is involved in AD-related molecular mechanisms, either as the primary cause of the disease or as a consequence of the disease; it seems therefore superfluous to state that further studies in this sense are warranted, both at genomic and at gene-specific level.

Many of the advances in the understanding of the role of epigenetic mechanisms in neurodegenerative disease started the first steps in AD research. One very recent example is represented by the studies on the role of the 5-hydroxymethylation in regulating gene expression [90]; these results shed new light on the role and the extent of hydroxymethylation have since shown the possibility that this, so far, underrepresented epigenetic modification may have a role in pathogenic processes. A second example is given by the studies about the theory, above-mentioned, that epigenetic changes may occur in the early life but become manifest in elderly. This theory in AD research has provided a fertile and rich field of intense study which developed the definition of the LEARn (Latent Early-life Associated Regulation) model [91]. According to this theory, environmental factors could poison the genome via epigenetic marks in the early phases of life, possibly even during the life in utero. This idea is in agreement with the generally accepted idea that neurodegenerative processes often start many years before the first appearance of clinical symptoms or evident molecular signs. At the same time, this concept offers the possibility to explore and monitor the interaction with the environment in the early life in an attempt to find efficient forms of prevention.

Due to the high variability shown by AD and other neurodegenerative diseases regarding the age of onset, the duration and severity of the progression and the severity of the symptoms, a very smart approach is represented by the studies on the monozygotic twins discordant for the occurrence of these diseases. Monozygotic twin siblings share the same genotype, but they frequently present phenotypic differences, such as their susceptibility to disease. Recent studies suggest that the main cause of the phenotypic discordance between monozygotic twins could have originated from epigenetic differences induced by different environmental factors encountered during their lifetime. A nice example is represented by studies on twins discordant for Lewy Body dementia, AD, Huntington’s disease and ataxia [92–94]; some differences among the healthy and diseased twin were represented by differences in their DNA methylation patterns.

Concluding remarks

To clarify the many dark points which still exist, the study of the role of DNA methylation and other epigenetic changes in neurodegenerative diseases requires research to take a different direction. On the one hand, more detailed studies on preclinical models and clinical samples could give further information on the molecular mechanisms inducing and regulating epigenetic changes and the exact role of these changes toward the mechanisms leading to the onset and the progression of the different diseases. On the other hand, the findings derived from preclinical studies should be verified on large cohorts of healthy and diseased subjects, in order to obtain significant clinical and epidemiological data. Furthermore, it will be necessary to study the sequence-specific epigenetic patterns and their modification in selected genes, but it will also be necessary to perform large-scale analyses to find other loci in the genome that are prone to epigenetic changes in the different diseases. In both cases, we will have to take advantage of the most recent advancement in the techniques for the study of DNA methylation and the other epigenetic changes.

This research will also help to clarify whether DNA methylation alterations (and epigenetic changes in general) are the cause of the disease or, in some cases, are associated with the disease as a consequence of the pathogenic status [95]. A comprehensive and very extensive review of the technical, clinical and experimental aspects related to the epigenetic relevance to human diseases has been recently collated in a book edited by T. Tollefsbol [96].

Corresponding author: Andrea Fuso, Department of Psychology, Section of Neuroscience, Sapienza University of Rome, Via dei Marsi, 78–00183 Rome, Italy

About the author

Andrea Fuso

Andrea Fuso, PhD, is Assistant Professor at Sapienza University of Rome within the Department of Psychology – Section of Neuroscience. He achieved his graduation in Biological Sciences at Sapienza University in 1997 and his PhD in Enzymology in 2001. He teaches at the post-graduation School of Clinical Pathology and at the School of Psychology at Sapienza University of Rome. His main research interest focuses on the one-carbon metabolism, with particular attention to DNA methylation mechanisms and their relationship with gene expression. In the field of basic science, he is interested in the dynamics of DNA methylation/demethylation patterns and the study of non-CpG methylation. As applicative fields, he studies the role of epigenetics, nutrition and one-carbon metabolism on Late Onset Alzheimer’s Disease and neurodegenerative diseases as well as in Rett syndrome, autism, neurodevelopment and muscle differentiation.

Conflict of interest statement

Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.


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Received: 2012-9-17
Accepted: 2012-10-19
Published Online: 2012-11-21
Published in Print: 2013-03-01

©2013 by Walter de Gruyter Berlin Boston

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