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CpG demethylation enhances alpha-synuclein expression and affects the pathogenesis of Parkinson's disease.

Matsumoto L, Takuma H, Tamaoka A, Kurisaki H, Date H, Tsuji S, Iwata A - PLoS ONE (2010)

Bottom Line: Gene multiplication can cause inherited PD, and promoter polymorphisms that increase SNCA expression are associated with sporadic PD.By using cultured cells, we identified a region of the SNCA CpG island in which the methylation status altered along with increased SNCA expression.This CpG region may function as an intronic regulatory element for SNCA gene.

View Article: PubMed Central - PubMed

Affiliation: Division of Neuroscience, Department of Neurology, Graduate School of Medicine, The University of Tokyo, Bunkyo, Tokyo, 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 SNCA expression influences PD pathogenesis.

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Related in: MedlinePlus

Analysis of CpG-2 methylation level in various brain regions.A–C: CpG-2 methylation was analyzed by bisulfite sequencing and plotted against age. Data from anterior cingulate cortex (control: n = 8, PD/DLB: n = 12) (A), putamen (control: n = 4, PD/DLB: n = 7) (B), and substantia nigra (control; n = 3, PD/DLB: n = 4) (C) are shown. Closed circle = controls, open box = PD/DLB. In figure 4C, age and % methylation had no significant correlation P = 0.2321. D–F: CpG-2 methylation was analyzed by bisulfite sequencing method and plotted by disease groups. Data from anterior cingulate cortex (D), putamen (E) and substantia nigra (F) are shown. Closed circle = controls, open box = PD, closed box = DLB P<0.0001 vs. control.
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pone-0015522-g004: Analysis of CpG-2 methylation level in various brain regions.A–C: CpG-2 methylation was analyzed by bisulfite sequencing and plotted against age. Data from anterior cingulate cortex (control: n = 8, PD/DLB: n = 12) (A), putamen (control: n = 4, PD/DLB: n = 7) (B), and substantia nigra (control; n = 3, PD/DLB: n = 4) (C) are shown. Closed circle = controls, open box = PD/DLB. In figure 4C, age and % methylation had no significant correlation P = 0.2321. D–F: CpG-2 methylation was analyzed by bisulfite sequencing method and plotted by disease groups. Data from anterior cingulate cortex (D), putamen (E) and substantia nigra (F) are shown. Closed circle = controls, open box = PD, closed box = DLB P<0.0001 vs. control.

Mentions: Bisulfite sequence analysis was performed for all available brain regions and the % methylation was plotted against various clinical parameters (Figures S1, S2, S3). When we compared methylation status of the anterior cingulated cortex and the putamen in controls and PD/DLB patients, there were no significant correlations (Figure 4A, B, D, E). However, methylation status of the substantia nigra was significantly lower in PD patients than in the controls (Figure 4F) and was unaffected by age (Figure 4C). Finally, we plotted % methylation against disease duration and found that in “normally” methylated DLB case, the disease duration was shorter than the PD cases (Figure 5A–C) suggesting extension of Lewy body pathology correlates with CpG-2 hypomethylation.


CpG demethylation enhances alpha-synuclein expression and affects the pathogenesis of Parkinson's disease.

Matsumoto L, Takuma H, Tamaoka A, Kurisaki H, Date H, Tsuji S, Iwata A - PLoS ONE (2010)

Analysis of CpG-2 methylation level in various brain regions.A–C: CpG-2 methylation was analyzed by bisulfite sequencing and plotted against age. Data from anterior cingulate cortex (control: n = 8, PD/DLB: n = 12) (A), putamen (control: n = 4, PD/DLB: n = 7) (B), and substantia nigra (control; n = 3, PD/DLB: n = 4) (C) are shown. Closed circle = controls, open box = PD/DLB. In figure 4C, age and % methylation had no significant correlation P = 0.2321. D–F: CpG-2 methylation was analyzed by bisulfite sequencing method and plotted by disease groups. Data from anterior cingulate cortex (D), putamen (E) and substantia nigra (F) are shown. Closed circle = controls, open box = PD, closed box = DLB P<0.0001 vs. control.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2991358&req=5

pone-0015522-g004: Analysis of CpG-2 methylation level in various brain regions.A–C: CpG-2 methylation was analyzed by bisulfite sequencing and plotted against age. Data from anterior cingulate cortex (control: n = 8, PD/DLB: n = 12) (A), putamen (control: n = 4, PD/DLB: n = 7) (B), and substantia nigra (control; n = 3, PD/DLB: n = 4) (C) are shown. Closed circle = controls, open box = PD/DLB. In figure 4C, age and % methylation had no significant correlation P = 0.2321. D–F: CpG-2 methylation was analyzed by bisulfite sequencing method and plotted by disease groups. Data from anterior cingulate cortex (D), putamen (E) and substantia nigra (F) are shown. Closed circle = controls, open box = PD, closed box = DLB P<0.0001 vs. control.
Mentions: Bisulfite sequence analysis was performed for all available brain regions and the % methylation was plotted against various clinical parameters (Figures S1, S2, S3). When we compared methylation status of the anterior cingulated cortex and the putamen in controls and PD/DLB patients, there were no significant correlations (Figure 4A, B, D, E). However, methylation status of the substantia nigra was significantly lower in PD patients than in the controls (Figure 4F) and was unaffected by age (Figure 4C). Finally, we plotted % methylation against disease duration and found that in “normally” methylated DLB case, the disease duration was shorter than the PD cases (Figure 5A–C) suggesting extension of Lewy body pathology correlates with CpG-2 hypomethylation.

Bottom Line: Gene multiplication can cause inherited PD, and promoter polymorphisms that increase SNCA expression are associated with sporadic PD.By using cultured cells, we identified a region of the SNCA CpG island in which the methylation status altered along with increased SNCA expression.This CpG region may function as an intronic regulatory element for SNCA gene.

View Article: PubMed Central - PubMed

Affiliation: Division of Neuroscience, Department of Neurology, Graduate School of Medicine, The University of Tokyo, Bunkyo, Tokyo, 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 SNCA expression influences PD pathogenesis.

Show MeSH
Related in: MedlinePlus