Dataset Information

PGC-1? Promoter Methylation in Parkinson's Disease.

ABSTRACT: The etiopathogenesis of sporadic Parkinson's disease (PD) remains elusive although mitochondrial dysfunction has long been implicated. Recent evidence revealed reduced expression of peroxisome proliferator-activated receptor gamma coactivator-1 ? (PGC-1?) and downstream regulated nuclear encoded respiratory complex genes in affected brain tissue from PD patients. We sought to determine whether epigenetic modification of the PGC-1? gene could account for diminished expression. In substantia nigra from PD patients but not control subjects, we show significant promoter-proximal non-canonical cytosine methylation of the PGC-1? gene but not an adjacent gene. As neuroinflammation is a prominent feature of PD and a mediator of epigenetic change, we evaluated whether the pro-inflammatory fatty acid, palmitate, would stimulate PGC-1? promoter methylation in different cell types from the CNS. Indeed, in mouse primary cortical neurons, microglia and astrocytes, palmitate causes PGC-1? gene promoter non-canonical cytosine methylation, reduced expression of the gene and reduced mitochondrial content. Moreover, intracerebroventricular (ICV) injection of palmitate to transgenic human ?-synuclein mutant mice resulted in increased PGC-1? promoter methylation, decreased PGC-1? expression and reduced mitochondrial content in substantia nigra. Finally we provide evidence that dysregulation of ER stress and inflammatory signaling is associated with PGC-1? promoter methylation. Together, these data strengthen the connection between saturated fatty acids, neuroflammation, ER stress, epigenetic alteration and bioenergetic compromise in PD.

SUBMITTER: Su X

PROVIDER: S-EPMC4552803 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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PGC-1α Promoter Methylation in Parkinson's Disease.

Su Xiaomin X Chu Yaping Y Kordower Jeffrey H JH Li Bin B Cao Hong H Huang Liang L Nishida Maki M Song Lei L Wang Difei D Federoff Howard J HJ

PloS one 20150828 8

The etiopathogenesis of sporadic Parkinson's disease (PD) remains elusive although mitochondrial dysfunction has long been implicated. Recent evidence revealed reduced expression of peroxisome proliferator-activated receptor gamma coactivator-1 α (PGC-1α) and downstream regulated nuclear encoded respiratory complex genes in affected brain tissue from PD patients. We sought to determine whether epigenetic modification of the PGC-1α gene could account for diminished expression. In substantia nigra ...[more]

PMID: 26317511

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Project description:Peroxisome proliferator-activated receptor-? co-activator (PGC)-1? is a transcriptional co-activator of antioxidant genes and a master regulator of mitochondrial biogenesis. Parkinson's disease (PD) is associated with oxidative stress and mitochondrial dysfunction and recent work suggests a role for PGC-1?. We hypothesized that the rs8192678 PGC-1? single nucleotide polymorphism (SNP) may influence risk or age of onset of PD. The A10398G mitochondrial SNP has been inversely associated with risk of PD in some studies. In the current study we analyzed whether rs8192678 or other PGC-1? SNPs affect PD risk or age of onset, singularly or in association with the A10398G SNP.Genomic DNA samples from 378 PD patients and 173 age-matched controls were analyzed by multiplexed probe sequencing, followed by statistical analyses of the association of each SNP, alone or in combination, with risk or age of onset of PD. Adjustments were made for age of onset being less than the age of sampling, and for the observed dependence between these two ages. The PD samples were obtained as two separate cohorts, therefore statistical methods accounted for different sampling methods between the two cohorts, and data were analyzed using Cox regression adjusted for sampling in the risk set definition and in the model.The rs8192678 PGC-1? SNP was not associated with the risk of PD. However, an association of the PGC-1? rs8192678 GG variant with longevity was seen in control subjects (p=0.019). Exploratory studies indicated that the CC variant of rs6821591 was associated with risk of early onset PD (p=0.029), with PD age of onset (p=0.047), and with longevity (p=0.022). The rs2970848 GG allele was associated with risk of late onset PD (p=0.027).These data reveal possible associations of the PGC-1? SNPs rs6821591 and rs2970848 with risk or age of onset of PD, and of the PGC-1? rs8192678 GG and the rs6821591 CC variants with longevity. If replicated in other datasets, these findings may have important implications regarding the role of PGC-1? in PD and longevity.

Dataset Information

PGC-1? Promoter Methylation in Parkinson's Disease.

Publications

PGC-1α Promoter Methylation in Parkinson's Disease.

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