Mechanisms of Programmed Cell Death in Parkinson's Disease and Multiple Sclerosis

Parkinson's disease (PD) and multiple sclerosis (MS) are neurodegenerative disorders with increasing global prevalence, yet early diagnosis and treatment remain significant challenges. Growing evidence implicates programmed cell death (PCD) in the pathogenesis of both diseases, though a systematic exploration of PCD-related molecular signatures across these conditions is still lacking. In this study, we integrated transcriptomic datasets with a curated set of 1,708 genes representing 13 PCD subtypes. Differential expression analysis identified disease-specific differentially expressed genes (DEGs), which significantly overlapped with PCD-related genes—more notably in MS than in PD. Functional enrichment analysis revealed distinct PCD pathway involvements: PD-related genes were enriched in mitochondrial outer membrane processes, intrinsic and extrinsic apoptosis, ferroptosis and p53 signaling, and MS-related genes highlighted lysosomal function, immune-mediated apoptosis and the PI3K-Akt pathway. Protein-protein interaction (PPI) network analysis revealed disease-specific hub genes, including JUN , TLR4 , IFNG and ERBB2 for PD, and AKT1 , IL1B and BCL2L1 for MS, with TLR4 and IFNG emerging as shared regulators. LASSO regression identified robust diagnostic gene panels (7 genes for PD, 5 for MS), and a random forest classifier validated their high predictive accuracy (AUC > 0.8) across independent cohorts. Immune infiltration analysis linked TLR4 to innate immune activation in PD and IFNG to cytotoxic responses in MS. Drug prediction identified potential therapeutic agents, such as muramyl dipeptide and carvedilol, targeting these hub genes. Our study characterizes both distinct and shared PCD landscapes in PD and MS, proposes novel diagnostic biomarkers, and highlights immunomodulatory and PCD-targeted therapeutic strategies, offering a comprehensive framework for advancing precision medicine in neurodegenerative diseases.