cpg demethylation enhances alpha-synuclein expression and affects the pathogenesis of parkinsons diseasecpg脱甲基作用提高α-突触核蛋白表达和影响帕金森病的发病机制.pdfVIP

CpG Demethylation Enhances Alpha-Synuclein Expression and Affects the Pathogenesis of Parkinson’s Disease 1 3 3 4 1 1 Lumine Matsumoto , Hiroshi Takuma , Akira Tamaoka , Hiroshi Kurisaki , Hidetoshi Date , Shoji Tsuji , Atsushi Iwata1,2,5* 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 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 S