Investigating cuproptosis and mitochondrial dysfunction in brain cells: uncovering novel mechanisms and biomarkers for Parkinson's disease.

Abstract

Parkinson's disease (PD) is a chronic neurodegenerative condition marked by the gradual degeneration of dopaminergic neurons, resulting in a range of disabling motor and non-motor symptoms. Despite advances, the molecular mechanisms underlying PD remain elusive, and effective biomarkers and therapeutic targets are limited. Recent studies suggest that mitochondrial dysfunction and dysregulated cellular metabolism are central to PD pathogenesis. This study investigated cuproptosis-related genes (CRGs), a class of genes linked to mitochondrial function and metabolic pathways, as potential contributors to PD using in silico and in vitro analyses. By analyzing Gene Expression Omnibus (GEO) datasets, we identified a consistent downregulation of CRGs, including DLD, FDX1, LIPT1, LIAS, PDHB, DLAT, PDHA1, CDKN2A, MTF1, and GLS, in PD samples. Immune infiltration analysis and subcellular localization studies highlighted significant correlations with immune cells and mitochondrial localization, implicating CRGs in immune and metabolic dysregulation. Functional assays confirmed that overexpression of DLD and FDX1 promotes cell proliferation and migration, suggesting their involvement in PD progression. Diagnostic model analysis further demonstrated the strong potential of CRGs as biomarkers, with high Area Under the Curve (AUC) values indicating accuracy in distinguishing PD from controls. Additionally, miRNA-mRNA interaction and drug sensitivity analyses identified key regulatory microRNAs (miRNAs) and drug sensitivities associated with CRGs expression. Pathway enrichment analysis linked CRGs to essential mitochondrial and metabolic processes, providing insights into PD's underlying mechanisms. The findings of this study emphasize the diagnostic and therapeutic potential of CRGs in PD, offering a novel avenue for understanding and managing this complex disease.