Abstract
Decreased expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is implicated in the pathophysiology of Parkinson’s disease (PD). However, our understanding of the mechanism regulating the PGC-1α expression is still limited. We sought to determine whether the epigenetic modification of PPARGC1A (the gene encoding PGC-1α) 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.
Highlights
Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder
It provides a bridge between the genes and the environment, and it may help to improve our understanding of the etiology of PD (Jakubowski and Labrie, 2017)
The concept of epigenetic regulation of gene expression is over 70 years old; DNA methylation is the most studied epigenetic modification and is known to alter gene expression in a heritable manner (Sweatt, 2013)
Summary
Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder. It is estimated that by 2030, Chinese PD patients will increase to 4.94 million, accounting for a half of the PD patients worldwide (Li et al, 2019). Recent advances have helped delineate the pathogenetic mechanisms, yet the etiology and pathogenesis of PD in most individuals remain obscure. Extensive genetic screening of families with PD has identified several mutations associated with PD. Environmental exposures have been suggested to play a crucial role in the etiological process of PD. It has been accepted that in most patients, the disease is caused by complicated interactions between genetic and environmental risk factors (Gao and Hong, 2011).
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