Fu Jia, Zhao Jing, Mi Na, Zhang Chao, Zhang Yali, Yao Lifen
Chifeng Municipal Hospital, Chifeng City, 024000, Inner Mongolia Autonomous Region, China.
The First Affiliated Hospital of Harbin Medical University, Harbin, 150080, Heilongjiang Province, China.
Mamm Genome. 2025 Jul 10. doi: 10.1007/s00335-025-10151-x.
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 = -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.
巴豆酰化及其代谢组学调控通路在帕金森病（PD）中的病理生理意义仍不清楚。我们利用孟德尔随机化（MR）框架结合中介分析来建立巴豆酰化相关基因与PD之间的因果联系，同时系统地描述代谢物介导的机制。在本研究中，从eQTLGen数据集中选择巴豆酰化相关基因，并使用两样本MR分析评估它们与PD的因果关系。随后，我们研究了与PD风险相关的代谢物。此外，应用两步MR和MR中介分析来探索巴豆酰化相关基因、代谢物和PD的中介作用。为了进一步解释细胞异质性，整合公开可用的GEO单细胞转录组数据以分析PD脑组织动态以及关键巴豆酰化相关基因的调控机制。我们鉴定出16个携带顺式eQTL的巴豆酰化相关基因，特别是SIRT1、GCDH和HDAC7，它们与PD风险呈显著负相关（p < 0.05）。通过MR分析，鉴定出74种与PD相关的代谢物。中介分析进一步表明，GCDH通过下调X - 21,471和十四烷二酸（C14 - DC）介导PD风险降低（β = -0.054）。此外，单细胞转录组分析显示，GCDH在PD脑组织中的星形胶质细胞中主要且特异性高表达，其动态调控模式与细胞分化过程密切相关，提示其可能通过NRG3 - ERBB4信号轴在调节PD发病机制中发挥作用。我们的研究结果表明，GCDH及其介导的代谢组对PD发病机制起着关键作用，星形胶质细胞成为核心调控细胞类型。本研究不仅阐明了PD病理背后的新分子格局，还突出了星形胶质细胞作为有前景的治疗干预靶点。
