Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra, leading to motor dysfunction and non-motor symptoms such as dementia, depression, and anxiety. Despite numerous studies on the prevention and treatment of PD, the causal relationships between plasma lipids, trace elements, cerebrospinal fluid (CSF) metabolites and PD remain unclear. This study employed Mendelian Randomization (MR) analysis using large European population samples to examine these relationships. We identified 17 lipid phenotypes, 2 trace elements (Selenium and Iridium), and 8 CSF metabolites that have a significant causal association with PD. Lipid phenotypes such as Triacylglycerol and Phosphatidylcholine were found to be protective against PD, while Sphingomyelin and other lipid types were identified as pathogenic. Selenium has been shown to have a protective effect, while Iridium is negatively associated with the progression of PD, suggesting a different role than other heavy metals.Our mediation analysis also revealed that these lipids could influence PD through their effects on CSF metabolites. For instance, Phosphatidylcholine and Uridine were found to protect neurons and improve PD prognosis, whereas no consistent mediation effect was observed for trace elements. Overall, our results provide new insights into the complex relationships between plasma lipids, trace elements and CSF metabolites and PD. These results offer potential pathways for future research and provide valuable information for the prevention and treatment of PD.

Parkinson’s disease (PD) involves not only the loss of dopaminergic neurons in the substantia nigra but also spinal cord degeneration. However, the molecular mechanisms of spinal cord degeneration remain unclear. This study investigated the spinal cord transcriptomic characteristics of MPTP-induced PD mice via transcriptome sequencing and weighted gene co-expression network analysis (WGCNA) to identify key gene modules and potential therapeutic targets. An MPTP-induced PD mouse model was established, and spinal cord transcriptome sequencing was conducted to screen differentially expressed genes (DEGs). Functional enrichment analysis, WGCNA for phenotype-correlated modules, and protein–protein interaction analysis were subsequently conducted to identify key genes. In total, 3473 DEGs were identified (1775 upregulated, 1698 downregulated). Downregulated genes were predominantly enriched in pathways related to oxidative phosphorylation and post-transcriptional regulation, whereas upregulated genes were associated with glutamatergic synapses, axonogenesis, and negative regulation of neurogenesis. Among the five co-expression modules, the brown and yellow modules were most strongly correlated with the PD phenotype, enriched in calcium signaling, inflammation, and spliceosome pathways. Key genes like Akt1, Nlrp3, Tgfb1, Lingo1, and Olig2 were upregulated, whereas Vps35 and Omg were downregulated. This study characterizes the spinal transcriptome of PD mice, suggesting that dysregulated post-transcriptional processes, abnormal oxidative phosphorylation, glutamatergic excitotoxicity, and neuroinflammation may be potential candidate mechanisms and vital involved factors in spinal cord degeneration. These findings provide novel insights into the pathological mechanisms of spinal cord degeneration in PD and lay a foundation for targeted therapy, deserving further investigation.