Multi-omic insight into the molecular mechanism of cuproptosis-related genes in the pathogenesis of Parkinson's disease.
Multi-omic insight into the molecular mechanism of cuproptosis-related genes in the pathogenesis of Parkinson's disease.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Hangzhou, CN · Author affiliation
Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.Location evidence
A plain-language reading has not been prepared for this paper yet.
Original abstract
Cuproptosis has been linked to Parkinson's disease (PD), but underlying genetic mechanisms remain unclear. We integrated multi-omic QTL data (methylation, gene expression, protein) with GWAS data of PD (discovery: GWAS Catalog; replication: UK Biobank/FinnGen/IEU). Integrated summary-data Mendelian randomization (SMR) with colocalization analyses revealed regulatory relationships involving 4 candidate genes (ISCA1, PDE6B, PTGES, and CERS2). Replication analyses demonstrated consistent CERS2/PDE6B methylation effects across cohorts. Experimental validation in MPTP-treated mice demonstrated that the copper chelator tetrathiomolybdate (TTM) robustly rescued motor deficits and prevented dopaminergic neurodegeneration. Mechanistically, TTM reversed core features of cuproptosis, including striatal copper accumulation and the destabilization of lipoylated TCA cycle proteins. TTM also normalized the expression of all four candidate genes, confirming a copper-dependent regulatory axis predicted by our SMR analysis. This study provides a functional link between cuproptosis-related genes and PD pathogenesis, highlighting copper dyshomeostasis as a key pathogenic driver and a potential therapeutic target.