Objective: We aimed to explore the hypothesis that the PGC-1α variants are associated with its promoter methylations level thus affecting the PGC-1α mRNA expression. We performed a study of PGC-1α risk-SNP genotypes, methylation levels, and mRNA expression in blood from PD patients and healthy controls.

Background: The epigenome provides a bridge between genes and environment and may help to improve our understanding on the etiology of PD. Recent evidence revealed reduced expression of PGC−1α in affected brain tissue and PBLs from PD patients [1,2]. However, the mechanism of regulating PGC-1α expression is still limited. Dysregulation of DNA methylation in PD patients is well documented. DNA methylation is known to alter gene expressionin a heritable manner. This raises the possibility that epigenetic modifications of the PGC−1α promoter may account for down-regulation of gene expression in PD.

Method: A total of 90 Chinese PD patients and 81 age- and gender-matched controls of Han ancestry were included in the study. PGC-1α promoter DNA methylation patterns and Single nucleotide polymorphisms (SNPs) of the PGC-1α were assessed using high-throughput mass spectrometry on a matrix-assisted laser desorption/ionization time-of-flight mass array. PGC-1α mRNA expression levels were detected in leukocytes.

Results: The mean DNA methylation level of PGC-1α intron-1 in PD patients was higher compared to controls (7.18±1.74 vs 6.36±1.28, p=0.007). We also found the PGC-1α mRNA level was significantly decreased in PD patients (2.85±3.30 vs 0.99±1.61, p=0.000). We found a significant negative correlation between the mean DNA methylation level of PGC-1α and PGC-1α mRNA levels (r=-0.448, p=0.000). There was a weak correlation between the mean methylation level and H-Y stage (r=0.207, p=0.050). However, there were no correlations between methylation level and clinical features including age of disease onset, disease duration, UPDRS III scores, HAMA, HAMD, MMSE, MoCA scores and LED. PGC-1α mean methylation level did not differ between different PGC-1α genotypes.

Conclusion: Taken together, our results revealed hypermethylation of PGC-1α in peripheral blood leukocytes of PD patients and confirmed the effect of DNA methylation of PGC-1α on its mRNA expression. These findings may contribute to better understanding of the mechanisms underlying the associations between PGC-1α and PD.

References: [1] J. Eschbach, E.B. von, K. Müller, et al. Mutual exacerbation of peroxisome proliferator-activated receptor γ coactivator 1α deregulation and α-synuclein oligomerization, Ann Neurol. 2015 Jan;77(1):15-32 [2] Xiaodong Yang, Yiwei Qian, Shaoqing Xu, et al. Expression of the gene coading for PGC-1α in peripheral blood leukocytes and related gene variants in patients with Parkinson’s disease, Parkinsonism Relat Disord, 2018 Jun;51:30-35.2

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MDS Abstracts - https://www.mdsabstracts.org/abstract/hypermethylation-of-pgc-1%ce%b1-in-peripheral-blood-leukocytes-of-patients-with-parkinsons-disease/