Multi-omic insight into the molecular mechanism of cuproptosis-related genes in the pathogenesis of Parkinson's disease.

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.