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

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          Abstract

          Background

          Alpha-synuclein ( SNCA) gene expression is an important factor in the pathogenesis of Parkinson's disease (PD). Gene multiplication can cause inherited PD, and promoter polymorphisms that increase SNCA expression are associated with sporadic PD. CpG methylation in the promoter region may also influence SNCA expression.

          Methodology/Principal Findings

          By using cultured cells, we identified a region of the SNCA CpG island in which the methylation status altered along with increased SNCA expression. Postmortem brain analysis revealed regional non-specific methylation differences in this CpG region in the anterior cingulate and putamen among controls and PD; however, in the substantia nigra of PD, methylation was significantly decreased.

          Conclusions/Significance

          This CpG region may function as an intronic regulatory element for SNCA gene. Our findings suggest that a novel epigenetic regulatory mechanism controlling SNCA expression influences PD pathogenesis.

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          Most cited references26

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          Epigenetics and aging: the targets and the marks.

          Mario Fraga, Manel Esteller (2007)
          'Aging epigenetics' is an emerging field that promises exciting revelations in the near future. Here we focus on the functional and biological significance of the epigenetic alterations that accumulate during aging and are important in tumorigenesis. Paradigmatic examples are provided by the global loss of DNA methylation in aging and cancer and by the promoter hypermethylation of genes with a dual role in tumor suppression and progeria, such as the Werner syndrome (WRN) and lamin A/C genes. Another twist is provided by sirtuins, a family of NAD-dependent deacetylases that act on Lys16 of histone H4, which are emerging as a link between cellular transformation and lifespan.
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            Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies.

            Rocio G. Urdinguio, Jose V Sanchez-Mut, Manel Esteller (2009)
            Epigenetic mechanisms such as DNA methylation and modifications to histone proteins regulate high-order DNA structure and gene expression. Aberrant epigenetic mechanisms are involved in the development of many diseases, including cancer. The neurological disorder most intensely studied with regard to epigenetic changes is Rett syndrome; patients with Rett syndrome have neurodevelopmental defects associated with mutations in MeCP2, which encodes the methyl CpG binding protein 2, that binds to methylated DNA. Other mental retardation disorders are also linked to the disruption of genes involved in epigenetic mechanisms; such disorders include alpha thalassaemia/mental retardation X-linked syndrome, Rubinstein-Taybi syndrome, and Coffin-Lowry syndrome. Moreover, aberrant DNA methylation and histone modification profiles of discrete DNA sequences, and those at a genome-wide level, have just begun to be described for neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, and in other neurological disorders such as multiple sclerosis, epilepsy, and amyotrophic lateral sclerosis. In this Review, we describe epigenetic changes present in neurological diseases and discuss the therapeutic potential of epigenetic drugs, such as histone deacetylase inhibitors.
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              Genomic 5-methyldeoxycytidine decreases with age.

              V Wilson, R Smith, S. Ma … (1987)
              Significant losses of DNA 5-methyldeoxycytidine residues in old age could disrupt cellular gene expression and contribute to the physiological decline of the animal. Thus, the 5-methyldeoxycytidine content of DNAs, isolated from the tissues of two rodent species of various ages, were determined. Mus musculus lost DNA methylation sites at a rate of about 4.7 X 10(4) (approximately 0.012% of the newborn level)/month. Peromyscus leucopus lost DNA 5-methyldeoxycytidine residues at a rate of only 2.3 X 10(4) (approximately 0.006% of the newborn level)/month. Since P. leucopus generally live twice as long as M. musculus, the rate of loss of DNA 5-methyldeoxycytidine residues appears to be inversely related to life span. Similar losses in genomic 5-methyldeoxycytidine content were also observed to correlate with donor age in cultured normal human bronchial epithelial cells.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2010
                Publication date (Electronic): 24 November 2010
                Volume: 5
                Issue: 11
                Electronic Location Identifier: e15522
                Affiliations
                [1 ]Division of Neuroscience, Department of Neurology, Graduate School of Medicine, The University of Tokyo, Bunkyo, Tokyo, Japan
                [2 ]Department of Molecular Neuroscience on Neurodegeneration, Graduate School of Medicine, The University of Tokyo, Bunkyo, Tokyo, Japan
                [3 ]Department of Neurology, University of Tsukuba, Tsukuba, Ibaraki, Japan
                [4 ]Department of Neurology, National Hospital Organization Tokyo Hospital, Kiyose, Tokyo, Japan
                [5 ]PRESTO, Japan Science and Technology Agency (JST), Kawaguchi, Saitama, Japan
                Brigham and Women's Hospital, Harvard Medical School, United States of America
                Author notes

                Conceived and designed the experiments: LM ST AI. Performed the experiments: LM HD AI. Analyzed the data: LM AI. Contributed reagents/materials/analysis tools: HT AT HK ST. Wrote the paper: LM HT AI.

                Article
                Publisher ID: PONE-D-10-00102
                DOI: 10.1371/journal.pone.0015522
                PMC ID: 2991358
                PubMed ID: 21124796
                SO-VID: d3da7d9b-931b-47ec-97f6-f16d93573c21
                Copyright © Matsumoto et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 2 August 2010
                Date accepted : 13 October 2010
                Page count
                Pages: 9
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Genetics
                Subject: Epigenetics
                Subject: DNA modification
                Subject: Gene Expression
                Subject: DNA modification
                Subject: Medicine
                Subject: Neurology
                Subject: Movement Disorders
                Subject: Neurodegenerative Diseases
                Subject: Parkinson Disease

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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