Aerobic Exercise Alleviates Oligodendrocyte Injury and Ferroptosis-Related Features in MPTP-Induced Parkinsonian Mice with Improved Neuropathological Phenotypes

Objectives: The pathological progression of Parkinson’s disease (PD) involves alterations across multiple neural cell types, and glial–neuronal communication substantially influences neuronal function. Oligodendrocytes (OLs) have been implicated in PD pathology, but the underlying regulatory mechanisms remain incompletely understood. Methods: In this study, single-nucleus RNA sequencing and spatial transcriptomics were used to characterize OL-associated changes and explore potentially relevant mechanisms in the substantia nigra pars compacta (SNpc) of MPTP-induced parkinsonian mice. Molecular validation was subsequently performed in an exercise intervention cohort. Results: These analyses revealed a significant reduction in OL abundance in the SNpc, accompanied by enrichment of ferroptosis-related pathways. Aerobic exercise partially restored the expression of the OL marker gene Plp1 and the antioxidant pathway-related molecules Nrf2 and Gpx4, while reducing ferroptosis-related oxidative stress. These changes were associated with improvements in PD-like pathological phenotypes. Exploratory untargeted metabolomics further identified candidate alterations in metabolites and pathways related to redox homeostasis, energy metabolism, and myelin-associated processes after MPTP treatment and exercise intervention. Conclusions: Collectively, exercise-associated improvements in MPTP-induced PD-like phenotypes coincided with reductions in OL/myelin-related injury and ferroptosis-related stress. These findings suggest that OL-associated ferroptosis-related stress may represent one of several processes contributing to neuronal injury in PD and may be responsive to aerobic exercise. This study provides a theoretical basis for further investigation of exercise-based rehabilitation strategies and potential therapeutic targets for PD.