Abstract
BackgroundAlpha-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 FindingsBy 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/SignificanceThis 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.
Highlights
Parkinson’s disease (PD) (MIM168600) is a neurodegenerative disease characterized by akinesia, rigidity, tremor, and postural instability
Our findings suggest that a novel epigenetic regulatory mechanism controlling SNCA expression influences PD pathogenesis
In rare cases of PD, duplication or triplication of SNCA gene leads to alphasynuclein accumulation, with triplication producing a more severe phenotype than duplication, suggesting that SNCA expression level determines the severity of the pathology [4,5,6]
Summary
Parkinson’s disease (PD) (MIM168600) is a neurodegenerative disease characterized by akinesia, rigidity, tremor, and postural instability. Most of the PD cases are sporadic, 10% is hereditary and caused by mutations in SNCA, PARK2, LRRK2, PINK1, UCHL1, or DJ1, in the majority of cases [2]. Abnormal accumulation of aggregated protein is closely associated with the pathogenesis of many neurodegenerative diseases. The precise mechanism of aggregation remains unknown, but increased expression of aggregation-prone proteins can lead to their aggregation. In Down syndrome, duplication of the 21st chromosome, which contains the amyloid beta precursor protein (APP) gene, leads to accumulation of amyloid beta and Alzheimer’s disease pathology [3]. 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 influence SNCA expression
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