Summary: Postmortem analysis of brain neurons from people with Parkinson’s disease identified over 200 genes showing altered epigenetic markers compared with healthy brains. Strikingly, the sets of affected genes differed almost entirely between women and men.
Source: Rutgers University
New Rutgers research, published in npj Parkinson’s Disease, shows that epigenetic changes associated with Parkinson’s disease differ by sex, suggesting distinct molecular profiles in men and women.
Researchers performed a genome-wide, postmortem study of neuronal DNA methylation, comparing parietal cortex samples from 50 individuals who died with mid-stage Parkinson’s and 50 matched controls without the disease. They identified more than 200 genes with differential epigenetic marks, but the specific genes altered in Parkinson’s cases were largely distinct between males and females.
“If you draw two circles representing genes with Parkinson’s-associated epigenetic changes — one for men and one for women — the overlap would be tiny: only about five genes,” said Alison Bernstein, senior author and assistant professor of pharmacology and toxicology at the Ernest Mario School of Pharmacy. “This pattern holds across human and animal studies, and across different models. What we call ‘Parkinson’s disease’ may actually encompass multiple sex-specific disease processes.”
Parkinson’s disease causes the progressive loss of neurons that produce dopamine, and while genetic mutations account for some cases, most arise from complex interactions among genetics, aging, and environmental exposures. Epigenetic marks, such as DNA methylation, are mechanisms that can link environmental and aging effects to changes in gene regulation without altering the underlying DNA sequence.
By isolating neurons from other cell types and analyzing male and female brains separately, the team uncovered sex-specific changes in DNA methylation at genes including PARK7 (DJ-1), SLC17A6 (VGLUT2), PTPRN2 (IA-2β), and NR4A2 (NURR1), along with many additional genes involved in neurotransmitter handling, neural development, and axon guidance.
Bernstein emphasized that these findings do not establish causation. “The altered epigenetic marks we observe may be a consequence of the disease rather than a cause,” she said. “We are conducting follow-up laboratory studies to determine whether particular epigenetic changes contribute directly to neuronal dysfunction and degeneration.”
Identifying genes and pathways that change early in Parkinson’s could reveal targets for interventions aimed at slowing or preventing progression. At present, clinical treatments like L-DOPA and other symptomatic therapies improve motor symptoms but do not halt the underlying neurodegenerative process. Understanding sex-specific molecular changes could guide more precise therapeutic strategies and improve clinical trial design.
Epidemiological data indicate Parkinson’s affects men more frequently than women in the United States and is the second most common neurodegenerative disorder after Alzheimer’s. While a minority of cases are attributable to known genetic mutations, the majority reflect a multifactorial interplay of aging, genetic susceptibility, and environmental risk factors such as prior brain injury or chemical exposures. Some lifestyle factors, including caffeine and nicotine use, have been associated with modestly lower Parkinson’s risk, but translating such associations into protective therapies remains challenging.
This study expands the catalog of candidate genes whose epigenetic regulation differs in Parkinson’s disease and highlights the importance of accounting for sex and cell type when studying the disorder. By focusing on enriched neuronal populations and separating male and female samples, the researchers aimed to reduce confounding from mixed cell populations and to reveal sex-specific molecular signatures that may otherwise be obscured in bulk tissue analyses.
About this epigenetics and Parkinson’s disease research news
Author: Press Office
Source: Rutgers University
Contact: Press Office – Rutgers University
Image: The image is in the public domain
Original Research: Open access. “Parkinson’s disease-associated, sex-specific changes in DNA methylation at PARK7 (DJ-1), SLC17A6 (VGLUT2), PTPRN2 (IA-2β), and NR4A2 (NURR1) in cortical neurons” by Joseph Kochmanski et al., npj Parkinson’s Disease
Abstract
Parkinson’s disease-associated, sex-specific changes in DNA methylation at PARK7 (DJ-1), SLC17A6 (VGLUT2), PTPRN2 (IA-2β), and NR4A2 (NURR1) in cortical neurons
Increasing evidence supports a role for epigenetic regulation, particularly DNA methylation, in Parkinson’s disease. Most Parkinson’s cases arise from a complex mix of aging, genetic predisposition, and environmental influences; epigenetic marks are prime candidates for mediating how these factors alter disease risk and progression.
Previous genome-wide methylation studies in Parkinson’s have been limited by analyses of bulk tissue and by failing to account for sex differences. Given the heterogeneity of brain samples and documented sex-related differences in Parkinson’s risk, progression, and severity, it is essential to consider both cell type and sex. This genome-wide analysis of neuronal DNA methylation in postmortem parietal cortex reveals sex-specific Parkinson’s-associated methylation changes in genes tied to synaptic transmission, neuronal development, and axon guidance, offering new avenues for research into mechanisms and potential therapeutic targets.