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

The 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.

We 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.

A total of 210 proteins significantly associated with PD were identified (p<0.05). Mediation analysis demonstrated that CCNE1 mediated 44.17% of the neuroprotective effect (β = -0.503, p = 5.8 × 10^-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 < 0.05), with neurons being significantly enriched in neural survival and synaptic plasticity pathways. The cell interaction network revealed that neurons specifically communicate with astrocytes via the NRG3-ERBB4 pathway.

This 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.