Hypermethylation of the Gene Coding for PGC-1α in Peripheral Blood Leukocytes of Patients With Parkinson's Disease

Decreased expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) is implicated in the pathophysiology of Parkinson's disease (PD). However, our understanding of the mechanism regulating the PGC-1 alpha expression is still limited. We sought to determine whether the epigenetic modification of PPARGC1A (the gene encoding PGC-1 alpha) could account for its diminished expression. We performed a study of PPARGC1A risk-SNP genotypes, methylation level, and the expression in blood from 171 subjects. The mean DNA methylation level of PPARGC1A intron 1 in patients with PD was higher than that in the controls (7.18 +/- 1.74 vs. 6.36 +/- 1.28, P = 0.007). A detailed comparison of the DNA methylation level at each CpG site showed that CpG_1, CpG_13.14, CpG_17.18, and CpG_20 were significantly hypermethylated in patients with PD. There was a significant negative correlation between PPARGC1A methylation and expression level (R = -0.404, P < 0.001). We found no correlations between the PPARGC1A methylation level and the clinical features, while the CpG_13.14 site methylation level was positively correlated with H&Y stage (R = 0.246, P = 0.020) and was increased in people carrying the rs2970848 AA genotype compared with that in carriers of the AG/GG genotype (7.27 +/- 1.86 vs. 6.65 +/- 1.92, P = 0.032). Our results support a link between PPARGC1A methylation, gene expression, and variability, which indicated that a novel epigenetic regulatory mechanism controlling PPARGC1A expression influences PD pathogenesis.