Parkinson’s disease (PD), the second most common neurodegenerative disorder, is characterized by dopaminergic neuron loss and glial dysregulation. Oligodendrocytes (OLs) support neuronal function through myelination, metabolic coupling, and trophic functions. However, their roles and regional vulnerability patterns in PD remain unclear. We reanalyzed a public single-nucleus RNA-seq dataset from the substantia nigra pars compacta of 29 individuals (15 with PD and 14 controls), together with an independent multi-region dataset comprising 100 individuals (75 with PD and 25 controls). After quality control, we performed clustering, differential expression, pathway enrichment, and cell–cell communication analyses, focusing on OL-specific transcriptomic alterations, subpopulation heterogeneity, and cell death–related programs. Cross-dataset validation and cell-type–resolved analyses were further performed to assess robustness and resolve regional heterogeneity. OLs had the highest scDist point estimate among the evaluated cell types. Upregulated OL genes showed proteostasis- and stress-related pathway enrichment, whereas downregulated genes were enriched in synaptic- and neuroactive ligand–receptor signaling pathways. An ALDH1A1-high OL subcluster showed metabolic reprogramming and ferroptosis activation. Cell-cell communication analysis revealed impaired neuron-OL interactions, with attenuation of neuronal NRG1-ERBB4 signaling. In the independent dataset, OLs consistently exhibited prominent transcriptional perturbations across brain regions. Across regions, OLs showed region-dependent enrichment of apoptosis- and necroptosis-related pathways, whereas MAPK signaling was consistently enriched. Cross-dataset analyses identify OLs as a prominently altered and regionally heterogeneous cell population in PD, with transcriptional patterns consistent with metabolic vulnerability, ferroptosis-related stress, altered MAPK signaling, and attenuated NRG1–ERBB4 neuron–OL communication.
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