CCNE1 Exerts a Protective Effect on Parkinson's Disease by Regulating Ferroptosis-Related Proteins.

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BackgroundThe pathogenesis of Parkinson's disease (PD) is closely linked to ferroptosis, yet the mechanism by which ferroptosis-related proteins modulate PD risk through genetic variations remains unclear.MethodsWe performed two-sample Mendelian randomization (MR) analyses using protein quantitative trait loci (pQTLs) from the UKB-PPP and deCODE studies as instrumental variables, combined with PD genome-wide association study (GWAS) data. The inverse variance weighting (IVW) method served as the primary analytical approach to identify PD-associated proteins. To assess the role of ferroptosis-related proteins in PD, a two-step MR mediation analysis was conducted, followed by multiple sensitivity analyses. Transcriptomic datasets were analyzed to confirm the differential expression of genes encoding prioritized proteins. Publicly available single-cell RNA sequencing data were utilized to investigate cell-type-specific expression patterns and functional pathways of key proteins.ResultsA total of 210 proteins significantly associated with PD were identified (p-4) through upregulating PARP16 expression (β = 0.318, p = 2.36 × 10-18), with CCNE1's differential expression further validated in transcriptomic datasets. Single-cell analysis demonstrated that CCNE1 and PARP16 are specifically highly expressed in neurons (p ConclusionThis study provides the first molecular insight into how CCNE1 exerts neuroprotective effects through the regulation of the ferroptosis key protein PARP16, offering a novel perspective for PD mechanism research.

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