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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

Dopamine induced demethylation of CpG-2.A: Location of CpGs in the second SNCA CpG island. There are 13 CpGs in the CpG-2 region. Each CpG is labeled above according to its positions from the 5′ end of the sequence. GATA transcription factor recognition sequence is shown with an under bar. B: Bisulfite sequence analysis of the CpG-2 region. Dopamine (DA; 0, 50, and 100 µM) was added to 293 cells. DNA was purified and bisulfite sequence analysis was performed. At least 20 clones from each dopamine-treated group were analyzed. Open circles indicate unmethylated CpGs, whereas closed circles indicate methylated CpGs. The degree of methylation was calculated as methylated CpG/total CpG and shown below (% methylation).
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pone-0015522-g002: Dopamine induced demethylation of CpG-2.A: Location of CpGs in the second SNCA CpG island. There are 13 CpGs in the CpG-2 region. Each CpG is labeled above according to its positions from the 5′ end of the sequence. GATA transcription factor recognition sequence is shown with an under bar. B: Bisulfite sequence analysis of the CpG-2 region. Dopamine (DA; 0, 50, and 100 µM) was added to 293 cells. DNA was purified and bisulfite sequence analysis was performed. At least 20 clones from each dopamine-treated group were analyzed. Open circles indicate unmethylated CpGs, whereas closed circles indicate methylated CpGs. The degree of methylation was calculated as methylated CpG/total CpG and shown below (% methylation).

Mentions: CpG-2 has 13 CpG sequences (Figure 2A). CpG-2 was 94.4% methylated at baseline, and decreased in a dose-dependent manner with the addition of dopamine (0 mM, 94.4%; 50 mM 72.0%; 100 mM 21.2%) (Figure 2B). Bisulfite sequencing analysis of CpG-1 revealed no significant change in methylation with the addition of dopamine (0 mM, 7.2%; 50 mM 3.3%; 100 mM 6.7%, figure not shown).


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)

Dopamine induced demethylation of CpG-2.A: Location of CpGs in the second SNCA CpG island. There are 13 CpGs in the CpG-2 region. Each CpG is labeled above according to its positions from the 5′ end of the sequence. GATA transcription factor recognition sequence is shown with an under bar. B: Bisulfite sequence analysis of the CpG-2 region. Dopamine (DA; 0, 50, and 100 µM) was added to 293 cells. DNA was purified and bisulfite sequence analysis was performed. At least 20 clones from each dopamine-treated group were analyzed. Open circles indicate unmethylated CpGs, whereas closed circles indicate methylated CpGs. The degree of methylation was calculated as methylated CpG/total CpG and shown below (% methylation).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2991358&req=5

pone-0015522-g002: Dopamine induced demethylation of CpG-2.A: Location of CpGs in the second SNCA CpG island. There are 13 CpGs in the CpG-2 region. Each CpG is labeled above according to its positions from the 5′ end of the sequence. GATA transcription factor recognition sequence is shown with an under bar. B: Bisulfite sequence analysis of the CpG-2 region. Dopamine (DA; 0, 50, and 100 µM) was added to 293 cells. DNA was purified and bisulfite sequence analysis was performed. At least 20 clones from each dopamine-treated group were analyzed. Open circles indicate unmethylated CpGs, whereas closed circles indicate methylated CpGs. The degree of methylation was calculated as methylated CpG/total CpG and shown below (% methylation).
Mentions: CpG-2 has 13 CpG sequences (Figure 2A). CpG-2 was 94.4% methylated at baseline, and decreased in a dose-dependent manner with the addition of dopamine (0 mM, 94.4%; 50 mM 72.0%; 100 mM 21.2%) (Figure 2B). Bisulfite sequencing analysis of CpG-1 revealed no significant change in methylation with the addition of dopamine (0 mM, 7.2%; 50 mM 3.3%; 100 mM 6.7%, figure not shown).

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