Table 11_Cuproptosis-associated genes DLD, ULK2, CCL8, and CCS link metabolic and immunological dysfunction in Parkinson’s disease: a multi-omics study.xlsx

The role of cuproptosis, a newly defined copper-dependent cell death pathway that is triggered during mitochondrial aerobic respiration, in PD remains incompletely understood. In this study, we employed integrated bioinformatics on bulk and single-cell RNA sequencing datasets to identify four hub cuproptosis-associated genes (DLD, ULK2, CCL8, and CCS) strongly linked to PD.

Functional enrichment and immune infiltration analyses linked these genes to metabolic disturbances and altered immune landscapes in PD. Single-cell transcriptomics further revealed patterns of cell-type-specific expression of these genes and altered inferred intercellular communication, particularly through the NRG signaling pathway between microglia and astrocytes. Experimental validation in AAV9-A53T α-synuclein mouse models, utilizing cell-type-specific multiplex immunofluorescence (mIF) and western blot analysis, provided supportive evidence for reduced DLD levels in dopaminergic neurons, decreased ULK2 and CCL8 expression in microglia, and diminished CCS content in astrocytes, accompanied by increased FDX1 expression in these cell populations.