[Abstract]
Decreased expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is implicated in the pathophysiology of Parkinson’s disease (PD). However, the mechanism of regulating PGC-1α expression remains unclear. In this study, we sought to explore whether 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 expression in blood from 171 subjects. The mean DNA methylation level of PPARGC1A intron 1 in patients with PD was higher than that in controls (7.18±1.74 vs. 6.36±1.28, P=0.007). A detailed comparison of DNA methylation level at each cytosine-guanine dinucleotide (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=0.000). We found no correlations between the PPARGC1A methylation level and 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 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 a novel epigenetic regulatory mechanism controlling PPARGC1A expression influences PD pathogenesis.
【中文摘要】
PGC-1α是一種重要的轉錄共激活因子，在帕金森病發病過程中發揮重要作用。課題組前期研究發現PGC-1α通過調節小膠質細胞極化，參與帕金森病發病過程，同時我們也發現帕金森病患者外周血中PGC-1α表達降低，更為重要的是PGC-1α的水平與帕金森病的嚴重程度呈負相關，提示我們增加PGC-1α的水平，對於帕金森病的治療可能有一定的幫助。為了進一步明確PGC-1α表達調控的機制。我們檢測了帕金森病患者外周血PGC-1α甲基化水平及表達水平，並進行了相關分析。我們入組了171例樣本(包括90名帕金森病患者及81名性別、年齡相匹配的健康對照)使用RT-qPCR方法檢測了外周血PGC-1α表達情況；使用基質輔助雷射解吸電離飛行時間質譜 (MALDI-TOF MS)方法，分析PGC-1α第一內含子22個CpG島甲基化水平及PGC-1α(rs2970848，rs2970870，rs6821591)基因多態性。探究PGC-1α甲基化水平與PGC-1α表達情況及其基因多態性的關係，進一步分析了PGC-1α甲基化水平與帕金森病臨床特徵的相關性。我們發現(1)帕金森病患者外周血PGC-1α第一內含子甲基化水平較健康對照明顯增高(7. 18±1.74 vs 6.36±1.28, P=0.007)，進一步分析發現CpG_1，CpG_13.14，CpG_ 17.18，CpG_20位點甲基化水平在帕金森病患者明顯增高。(2)PGC-1α第一內含子甲基化水平與PGC-1α表達呈負相關(R=-0.404, P=0.000)。(3)PGC-1α 第一內含子CpG_13.14位點甲基化水平與H-Y分期相關(R=0.246, P=0.020)，並且攜帶rs2970848 AA基因型的患者較攜帶AG/GG 基因型的患者CpG_13.14位點甲基化水平增高(7.27±1.86 vs 6.65±1.92 , P=0.032)。