Integrative multiomics elucidate crotonylation-associated GCDH in Parkinson's disease pathogenesis via metabolome remodeling.

The pathophysiological significance of crotonylation and its metabolomic regulatory circuitry in Parkinson's disease (PD) remains elusive. We utilized Mendelian randomization (MR) frameworks combined with mediation analysis to establish causal links between crotonylation-associated genes and PD, while systematically delineating metabolite-mediated mechanisms. In this study, crotonylation-related genes were selected from the eQTLGen dataset, and their causal relationship with PD was assessed using two-sample MR analysis. Subsequently, we investigated metabolites associated with PD risk. Additionally, two-step MR and MR mediation analyses were applied to explore the mediating effects of crotonylation-related genes, metabolites, and PD. To further interpret cellular heterogeneity, publicly available GEO single-cell transcriptome data were integrated to analyze PD brain tissue dynamics and the regulatory mechanisms of key crotonylation-related genes. We identified 16 crotonylation-associated genes harboring cis-eQTLs, notably SIRT1, GCDH, and HDAC7, which demonstrated significant inverse associations with PD risk (p < 0.05). Through MR analysis, 74 PD-associated metabolites were identified. Mediation analysis further delineated GCDH-mediated PD risk reduction (β_all = -0.054) through downregulation of X-21,471 and tetradecanedioate (C14-DC). Furthermore, single-cell transcriptomic analysis revealed that GCDH is predominantly and specifically highly expressed in astrocytes within PD brain tissues, and its dynamic regulatory pattern is closely linked to cell differentiation processes, suggesting a potential role in regulating PD pathogenesis via the NRG3-ERBB4 signaling axis. Our findings indicate that GCDH and its mediated metabolome critically contribute to PD pathogenesis, with astrocytes emerging as a central regulatory cell type. This study not only elucidates novel molecular landscapes underlying PD pathology but also highlights astrocytes as promising targets for therapeutic intervention.