Epigenetic Gene-Environment Interactions in Parkinson’s Disease

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder, characterized by the progressive loss of dopaminergic neurons in the substantia nigra. While genetic mutations and environmental exposures have both been established as risk factors for PD, emerging evidence has implicated epigenetic modifications as key mediators of gene-environment interactions involved in the pathogenesis of PD. Objective: This review aims to systematically characterize the epigenetic regulatory mechanisms that bridge the effects of environmental neurotoxicants and genetic susceptibility in PD, providing a comprehensive synthesis of the current understanding of their functional crosstalk at a molecular level. Key Findings: Environmental factors drive the pathogenesis of PD through abnormal DNA methylation, dynamic imbalances in histone modification, and non-coding RNA regulatory networks. Here, we detail the mechanisms by which environment-induced epigenetic shifts give rise to the dysregulation of key PD-associated genes, including SNCA, PRKN (PARK2), PARK7 (DJ-1), and LRRK2. This epigenetic dysregulation subsequently exacerbates downstream pathological events, such as mitochondrial dysfunction, impaired autophagy, endoplasmic reticulum stress, and neuroinflammation. Conclusion: Systematically exploring epigenetic gene-environment interactions offers detailed insight into the etiology of PD. Given the potential reversibility of specific epigenetic modifications, targeting these pathways may offer a prospective avenue for neuroprotective research. However, further rigorous investigation remains essential to evaluate the clinical viability of these mechanisms as reliable biomarkers or therapeutic targets.