{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T05:18:33Z","timestamp":1787721513668,"version":"build-2784847793"},"reference-count":39,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sci.","Brain Sciences"],"abstract":"<jats:p>Objectives: The pathological progression of Parkinson\u2019s disease (PD) involves alterations across multiple neural cell types, and glial\u2013neuronal 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.<\/jats:p>","DOI":"10.3390\/brainsci16090904","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T14:49:34Z","timestamp":1787582974000},"page":"904","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Aerobic Exercise Alleviates Oligodendrocyte Injury and Ferroptosis-Related Features in MPTP-Induced Parkinsonian Mice with Improved Neuropathological Phenotypes"],"prefix":"10.3390","volume":"16","author":[{"given":"Min","family":"Yan","sequence":"first","affiliation":[{"name":"School of Sports and Health, Tianjin Sport University, Tianjin 301617, China"},{"name":"Academy of Sports Sciences, Shandong Sport University, Jinan 250102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Academy of Sports Sciences, Shandong Sport University, Jinan 250102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zigui","family":"Zhou","sequence":"additional","affiliation":[{"name":"Academy of Sports Sciences, Shandong Sport University, Jinan 250102, China"},{"name":"School of Sports and Health, Shanghai Sport University, 650 Qingyuan Road, Shanghai 200438, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changzhi","family":"Yang","sequence":"additional","affiliation":[{"name":"Academy of Sports Sciences, Shandong Sport University, Jinan 250102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuewen","family":"Tian","sequence":"additional","affiliation":[{"name":"Academy of Sports Sciences, Shandong Sport University, Jinan 250102, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peijie","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Sports and Health, Tianjin Sport University, Tianjin 301617, China"},{"name":"School of Sports and Health, Shanghai Sport University, 650 Qingyuan Road, Shanghai 200438, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e464","DOI":"10.1016\/S2666-7568(24)00094-1","article-title":"Temporal trends in the prevalence of Parkinson\u2019s disease from 1980 to 2023: A systematic review and meta-analysis","volume":"5","author":"Zhu","year":"2024","journal-title":"Lancet Healthy Longev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1016\/S0140-6736(21)00218-X","article-title":"Parkinson\u2019s disease","volume":"397","author":"Bloem","year":"2021","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S1474-4422(06)70373-8","article-title":"Non-motor symptoms of Parkinson\u2019s disease: Diagnosis and management","volume":"5","author":"Chaudhuri","year":"2006","journal-title":"Lancet Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.parkreldis.2019.01.015","article-title":"Co-morbid demyelinating lesions and atypical clinical features in a patient with Parkinson\u2019s disease","volume":"62","author":"Vilas","year":"2019","journal-title":"Park. Relat. Disord."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1002\/mds.28393","article-title":"Oligodendrocytes, a new player in the etiology of Parkinson\u2019s disease","volume":"36","author":"Errea","year":"2021","journal-title":"Mov. Disord."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1093\/brain\/awab446","article-title":"Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state","volume":"145","author":"Landoulsi","year":"2022","journal-title":"Brain"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.molmed.2022.02.003","article-title":"Ferroptosis in Parkinson\u2019s disease: Glia\u2013neuron crosstalk","volume":"28","author":"Wang","year":"2022","journal-title":"Trends Mol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"18889","DOI":"10.18632\/aging.103935","article-title":"Increased expression of myelin-associated genes in frontal cortex of SNCA overexpressing rats and Parkinson\u2019s disease patients","volume":"12","author":"Hentrich","year":"2020","journal-title":"Aging"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1002\/glia.20784","article-title":"Oligodendrocytes and myelination: The role of iron","volume":"57","author":"Todorich","year":"2009","journal-title":"Glia"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.tins.2019.03.009","article-title":"Iron, myelin, and the brain: Neuroimaging meets neurobiology","volume":"42","author":"Bossoni","year":"2019","journal-title":"Trends Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"9327","DOI":"10.1523\/JNEUROSCI.1749-20.2020","article-title":"Ferroptosis mediates cuprizone-induced loss of oligodendrocytes and demyelination","volume":"40","author":"Jhelum","year":"2020","journal-title":"J. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"117419","DOI":"10.1016\/j.biopha.2024.117419","article-title":"The role of iron transporters and regulators in Alzheimer\u2019s disease and Parkinson\u2019s disease: Pathophysiological insights and therapeutic prospects","volume":"179","author":"Tian","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Xu, Y., Jia, B., Li, J., Li, Q., and Luo, C. (2024). The Interplay between Ferroptosis and Neuroinflammation in Central Neurological Disorders. Antioxidants, 13.","DOI":"10.3390\/antiox13040395"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1007\/s00702-020-02167-1","article-title":"Parkinson\u2019s disease treatment: Past, present, and future","volume":"127","author":"Elsworth","year":"2020","journal-title":"J. Neural Transm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"117345","DOI":"10.1016\/j.lfs.2020.117345","article-title":"The benefits and mechanisms of exercise training for Parkinson\u2019s disease","volume":"245","author":"Feng","year":"2020","journal-title":"Life Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"103143","DOI":"10.1016\/j.redox.2024.103143","article-title":"Lipoxin A4 ameliorates knee osteoarthritis progression in rats by antagonizing ferroptosis through activation of the ESR2\/LPAR3\/Nrf2 axis in synovial fibroblast-like synoviocytes","volume":"73","author":"Hu","year":"2024","journal-title":"Redox Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"103079","DOI":"10.1016\/j.redox.2024.103079","article-title":"Endurance exercise preconditioning alleviates ferroptosis induced by doxorubicin-induced cardiotoxicity through mitochondrial superoxide-dependent AMPK\u03b12 activation","volume":"70","author":"Wang","year":"2024","journal-title":"Redox Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1038\/s41593-022-01221-3","article-title":"Microglia ferroptosis is regulated by SEC24B and contributes to neurodegeneration","volume":"26","author":"Ryan","year":"2023","journal-title":"Nat. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.4103\/1673-5374.373683","article-title":"Role of exercise in the brain: Focus on oligodendrocytes and remyelination","volume":"18","author":"Maugeri","year":"2023","journal-title":"Neural Regen. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/s41398-019-0662-8","article-title":"Running exercise protects oligodendrocytes in the medial prefrontal cortex in chronic unpredictable stress rat model","volume":"9","author":"Luo","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.brainresbull.2021.06.024","article-title":"Treadmill exercise alleviates neuronal damage by suppressing NLRP3 inflammasome and microglial activation in the MPTP mouse model of Parkinson\u2019s disease","volume":"174","author":"Wang","year":"2021","journal-title":"Brain Res. Bull."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/s41531-025-00912-5","article-title":"Voluntary exercise alleviates neural functional deficits in Parkinson\u2019s disease mice by inhibiting microglial ferroptosis via SLC7A11\/ALOX12 axis","volume":"11","author":"Xu","year":"2025","journal-title":"npj Park. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.neuroscience.2018.03.015","article-title":"Endurance Exercise Mediates Neuroprotection Against MPTP-mediated Parkinson\u2019s Disease via Enhanced Neurogenesis, Antioxidant Capacity, and Autophagy","volume":"379","author":"Jang","year":"2018","journal-title":"Neuroscience"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Yang, Q., and Zhuang, C. (2025). Research progress on the role of exercise-regulated reactive astrocytes in the prevention and treatment of Parkinson\u2019s disease. Front. Aging Neurosci., 17.","DOI":"10.3389\/fnagi.2025.1561006"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.tins.2023.11.003","article-title":"White matter injury across neurodegenerative disease","volume":"47","author":"Festa","year":"2024","journal-title":"Trends Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/s41583-023-00744-3","article-title":"Neuron-oligodendroglial interactions in health and malignant disease","volume":"24","author":"Taylor","year":"2023","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"111076","DOI":"10.1016\/j.brainresbull.2024.111076","article-title":"Investigating the mechanisms of inflammation and immune alterations in Parkinson\u2019s disease using spatial transcriptomics techniques","volume":"217","author":"Zhang","year":"2024","journal-title":"Brain Res. Bull."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Liu, Q., Liu, Z., Xie, W., Li, Y., Wang, H., Zhang, S., Wang, W., Hao, J., Geng, D., and Yang, J. (2024). Single-cell sequencing of the substantia nigra reveals microglial activation in a model of MPTP. Front. Aging Neurosci., 16.","DOI":"10.3389\/fnagi.2024.1390310"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Han, S., Gim, Y., Jang, E.H., and Hur, E.-M. (2022). Functions and dysfunctions of oligodendrocytes in neurodegenerative diseases. Front. Cell. Neurosci., 16.","DOI":"10.3389\/fncel.2022.1083159"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Cui, S., Wang, S., Liu, M., Zou, Q., Cai, Z., and Ma, J. (2026). Enhancing oligodendrocytes generation and myelin renewal by vitamin C mitigate Parkinson-relevant phenotypes in a murine model of Parkinson\u2019s disease. Front. Cell. Neurosci., 20.","DOI":"10.3389\/fncel.2026.1761155"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"115266","DOI":"10.1016\/j.celrep.2025.115266","article-title":"Oligodendrocytes drive neuroinflammation and neurodegeneration in Parkinson\u2019s disease via the prosaposin-GPR37-IL-6 axis","volume":"44","author":"Ma","year":"2025","journal-title":"Cell Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2136","DOI":"10.14336\/AD.2024.0216","article-title":"Physical Exercise Counteracts Aging-Associated White Matter Demyelination Causing Cognitive Decline","volume":"15","author":"Butt","year":"2024","journal-title":"Aging Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.1016\/j.cell.2024.04.005","article-title":"Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration","volume":"187","author":"Liu","year":"2024","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.celrep.2016.09.030","article-title":"Voluntary Running Triggers VGF-Mediated Oligodendrogenesis to Prolong the Lifespan of Snf2h-Null Ataxic Mice","volume":"17","author":"Yang","year":"2016","journal-title":"Cell Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/s41593-023-01558-3","article-title":"Oligodendrocyte-axon metabolic coupling is mediated by extracellular K(+) and maintains axonal health","volume":"27","author":"Looser","year":"2024","journal-title":"Nat. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"101890","DOI":"10.1016\/j.pneurobio.2020.101890","article-title":"Ferroptosis and its potential role in the physiopathology of Parkinson\u2019s Disease","volume":"196","author":"Bouchaoui","year":"2021","journal-title":"Prog. Neurobiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s40478-021-01145-2","article-title":"Cell specific quantitative iron mapping on brain slices by immuno-\u00b5PIXE in healthy elderly and Parkinson\u2019s disease","volume":"9","author":"Friedrich","year":"2021","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Jung, H.Y., Kwon, H.J., Kim, W., Hwang, I.K., Choi, G.-M., Chang, I.B., Kim, D.W., and Moon, S.M. (2021). Tat-Endophilin A1 Fusion Protein Protects Neurons from Ischemic Damage in the Gerbil Hippocampus: A Possible Mechanism of Lipid Peroxidation and Neuroinflammation Mitigation as Well as Synaptic Plasticity. Cells, 10.","DOI":"10.3390\/cells10020357"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"107179","DOI":"10.1016\/j.intimp.2020.107179","article-title":"Ferrostatin-1 alleviates angiotensin II (Ang II)-induced inflammation and ferroptosis in astrocytes","volume":"90","author":"Li","year":"2021","journal-title":"Int. Immunopharmacol."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/9\/904\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T04:18:59Z","timestamp":1787717939000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/9\/904"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,24]]},"references-count":39,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["brainsci16090904"],"URL":"https:\/\/doi.org\/10.3390\/brainsci16090904","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,24]]}}}