Identifying potential genes driving ferroptosis in the substantia nigra and dopaminergic neurons in Parkinson's disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder marked by dopaminergic (DA) neuron degeneration in the substantia nigra (SN). Conventional dopamine replacement therapies provide limited long-term efficacy and significant side effects. Emerging evidence suggests ferroptosis—a form of cell death driven by iron-dependent lipid peroxidation—contributes to PD pathology, though direct evidence linking dysregulation of ferroptosis-related genes in DA neuron loss in PD remains limited. This study explores the expression of ferroptosis-associated genes in the SN and DA neurons of PD patients, identifying potential therapeutic targets. We analyzed two independent RNA-seq datasets, GSE7621 and GSE8397 (GPL-96), from the GEO database to identify common differentially expressed ferroptosis-related genes in the SN of PD patients. We also conducted Gene Ontology and pathway enrichment analyses of these genes to explore the underlying mechanisms and constructed a protein-protein interaction network. The findings were further validated using an additional dataset, GSE49036. We further explored the dysregulation of these ferroptosis-related genes in DA neurons using RNA-seq data GSE169755, derived from DA neurons isolated from the SN of PD patients and controls. Lastly, the proposed hypothesis was experimentally validated in an in vitro PD model. This comprehensive multi-dataset analysis uncovers novel insights into the expression of ferroptosis-related genes in PD, suggesting potential biomarkers and therapeutic targets for mitigating DA neuron loss and PD progression.