{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:19:54Z","timestamp":1787026794078,"version":"build-2736575974"},"reference-count":102,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>Oligodendrocyte lineage cells, consisting of mature oligodendrocytes (mOLs) and their progenitors (OPCs), sustain myelination and support axonal metabolic integrity in the mammalian central nervous system. In neurodegenerative disorders, functional deficits spanning impaired mOL homeostasis and dysregulated OPC activation are no longer regarded as passive secondary outcomes of neuronal injury. Instead, emerging clinical and preclinical data demonstrate that oligodendroglial dysfunction actively fuels disease progression. Notably, most human evidence remains correlative, with few definitive proofs that OL pathology initiates neurodegeneration, indicating lineage malfunction predominantly exacerbates, rather than triggers, disease onset across Alzheimer's, Parkinson's, and Huntington's diseases. In this review, we synthesize disease-specific oligodendrocyte pathological signatures and context-dependent cellular responses, focusing on underrecognized OL-intrinsic pathogenic mechanisms: endogenous A\u03b2 production, aberrant protein aggregation, disrupted cholesterol turnover, and excessive neuroinflammatory amplification. We further establish a unified mechanistic model to explain the widespread heterogeneity of white matter pathology across distinct neurodegenerative contexts. We detail four core interconnected pathways whereby defective OL lineage function drives tissue deterioration: myelin loss and progressive axonal degeneration, disrupted neuroimmune homeostasis, cytotoxicity from aggregated pathological proteins, and dysregulated metabolic signaling. To resolve persistent conceptual confusion in the field, we strictly distinguish cell-autonomous primary oligodendroglial lesions, secondary reactive changes following neuronal damage, and non-specific white matter remodeling. We also address critical translational barriers stemming from well-documented phenotypic discrepancies between animal models and human patient brains. Moreover, we consolidate current OL-targeted therapeutic strategies, including myelin restoration, immunomodulatory intervention, metabolic reprogramming, and gene-targeted therapy, highlighting the clinical bottlenecks of single-target regimens and the superior translational prospects of multi-target combinatorial strategies. We conclude by outlining key unresolved challenges and future research avenues, covering OL subtype identification, intercellular signaling crosstalk characterization, humanized model optimization, and precision delivery technique innovation. Collectively, this review refines our understanding of context-dependent oligodendrocyte biofunctions in neurodegeneration, clarifies the origin and consequence of white matter lesions, and offers actionable mechanistic and theoretical support for developing novel glia-based clinical therapies.<\/jats:p>","DOI":"10.3389\/fnagi.2026.1843643","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T05:41:52Z","timestamp":1778823712000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Oligodendrocyte dysfunction in neurodegenerative diseases: pathological features, underlying mechanisms and therapeutic targeting"],"prefix":"10.3389","volume":"18","author":[{"given":"Zizhen","family":"Liu","sequence":"first","affiliation":[{"name":"College of Basic Medicine, Qilu Medical University, Zibo","place":["Shandong, China"]},{"name":"College of Sport and Health, Shandong Sport University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Basic Medicine, Qilu Medical University, Zibo","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjing","family":"Liang","sequence":"additional","affiliation":[{"name":"College of Sport and Health, Shandong Sport University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Meng","sequence":"additional","affiliation":[{"name":"College of Basic Medicine, Qilu Medical University, Zibo","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinglu","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Sport and Health, Shandong Sport University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Zibo Central Hospital","place":["Zibo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibin","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Basic Medicine, Qilu Medical University, Zibo","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1420","DOI":"10.1007\/s12015-026-11061-4","article-title":"Human myelin spheres for in vitro oligodendrocyte maturation, myelination and neurological disease modeling","volume":"22","author":"Ahuja","year":"2026","journal-title":"Stem Cell Rev. 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