CpG Demethylation Enhances Alpha-Synuclein Expression and Affects the Pathogenesis of Parkinson's Disease

Matsumoto, Lumine; Takuma, Hiroshi; Tamaoka, Akira; Kurisaki, Hiroshi; Date, Hidetoshi; Tsuji, Shoji; Iwata, Atsushi

doi:10.1371/journal.pone.0015522

Cited by 286 publications

(237 citation statements)

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“…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 ].…”

Section: Dna Methylation and Neurodegenerationmentioning

confidence: 97%

The ‘golden age’ of DNA methylation in neurodegenerative diseases

Fuso¹

2013

Clinical Chemistry and Laboratory Medicine

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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 seve ral 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.

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Section: Dna Methylation and Neurodegenerationmentioning

confidence: 97%

The ‘golden age’ of DNA methylation in neurodegenerative diseases

Fuso¹

2013

Clinical Chemistry and Laboratory Medicine

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“…A number of recent studies have shown that the expression level of the gene encoding α-syn is regulated through epigenetic mechanisms, through a methylated CpG in intron 1 and through HDAC activity (Du et al, 2010;Jowaed et al, 2010;Matsumoto et al, 2010) (Fig. 5A).…”

Section: Epigenetic Control Of and By α-Synucleinmentioning

confidence: 99%

Epigenetic mechanisms in the development and maintenance of dopaminergic neurons

et al. 2013

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SummaryMesodiencephalic dopaminergic (mdDA) neurons are located in the ventral mesodiencephalon and are involved in psychiatric disorders and severely affected in neurodegenerative diseases such as Parkinson's disease. mdDA neuronal development has received much attention in the last 15 years and many transcription factors involved in mdDA specification have been discovered. More recently however, the impact of epigenetic regulation has come into focus, and it's emerging that the processes of histone modification and DNA methylation form the basis of genetic switches that operate during mdDA development. Here, we review the epigenetic control of mdDA development, maturation and maintenance. As we highlight, epigenetic mechanisms play a pivotal role in all of these processes and the knowledge gathered from studying epigenetics in these contexts may aid our understanding of mdDA-related pathologies. Key words: Brain, Development, Dopamine, Epigenetics, Gene regulation, Midbrain IntroductionIf you turn this page, both the decision you make and the action that you carry out are significantly influenced by the amount of dopamine (DA; see Glossary, Box 1) released from dopaminergic neurons within your brain. Mesodiencephalic dopaminergic (mdDA) neurons located in the substantia nigra pars compacta (SNc; see Glossary, Box 1), in particular, are essential for motor functions whereas mdDA neurons of the ventral tegmental area (VTA; see Glossary, Box 1) and the retrorubal field (RRF; see Glossary, Box 1) are involved in the regulation of emotions and reward . Notably, severe loss of SNc mdDA neurons is a pathological hallmark of Parkinson's disease (PD) (Sulzer, 2007). By contrast, mdDA neurons in the VTA and RRF, which remain intact in PD, are part of the mesocorticolimbic system (see Glossary, Box 1), in which defective DA neurotransmission has been implicated in the development of drug addiction, depression and schizophrenia (Nestler, 2000). Given their involvement in neurodegenerative diseases and psychiatric disorders, mdDA neurons have been studied intensively in recent years.In the last two decades, a variety of molecular approaches have revealed factors that are specific for mdDA neuronal subsets or that guide their spatial organization ; recently, a pathway that molecularly distinguishes SNc DA neurons from those located in the VTA was identified (Jacobs et al., 2011). In addition to molecular profiling of DA neurons, however, a second level of complexity has been added by the rapidly emerging field of epigenetics, which has provided new insights into the origin and maintenance of distinctive gene expression patterns in mdDA neurons. Current definitions of epigenetics often emphasize the heritability of changes in gene expression throughout cell divisions that are not due to alterations in DNA sequence. However, perhaps a more appropriate definition of epigenetics, especially when applying this term to mature neurons that cannot divide, is postulated by Adrian Bird: 'The structural adaptation of chromosomal regio...

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“…Although the role of DNA methylation and its link to PD pathogenesis is currently unclear, methylation of the SNCA gene may be involved in pathology via structural changes or the overexpression of the protein, leading to protein aggregation, or via impaired gene expression. Methylation of SNCA intron 1 has been demonstrated to be associated with decreased SNCA transcription, whereas reduced methylation at this site was found to be decreased in several brain regions, including the substantia nigra, of sporadic PD patients, causing the increased expression of the SNCA gene [23,24]. These results raise the possibility that the increased α-synuclein production that is associated with PD may result from increased SNCA expression, as a consequence of a decreased methylation state of the SNCA gene.…”

Section: Epigenetic Modulation In Familial Parkinson's Diseasementioning

confidence: 92%