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REVIEW ARTICLE

Demyelination in Parkinson’s disease: Not just a secondary bystander, but also as an active contributor to pathogenesis

Obinna O. Uchewa1* ,  Ejiofor J. Alobu1 ,  Joy O. Nwofia1 ,  Augustine O. Ibegbu1
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1 Department of Anatomy, Faculty of Basic Medical Sciences, Alex Ekwueme Federal University, Ndufu-Alike, Ebonyi, Nigeria
Advanced Neurology, 025510128 https://doi.org/10.36922/AN025510128
Received: 18 December 2025 | Revised: 11 March 2026 | Accepted: 12 March 2026 | Published online: 15 May 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Parkinson’s disease (PD) primarily affects the gray matter, with a gradual loss of dopaminergic neurons in the substantia nigra and the buildup of intraneuronal α-synuclein. Recent neuroimaging and neuropathological studies have indicated widespread alterations in white matter microstructure, raising a vital question: Is demyelination merely a consequence of axonal degeneration, or does it actively drive neurodegeneration? This review discusses the role of demyelination in PD and highlights future research directions. A literature search was conducted using keywords such as “myelin,”“demyelination,” “bystander,” “remyelination,” “impact of demyelination,” “causes of Parkinson’s,” Parkinson’s disease,” “myelination,” “functional magnetic resonance imaging,” “neurodegeneration,” “factors affecting Parkinson’s,” “PD,” “α-synuclein,” “synucleinopathy,” and “aging” across Scopus, Web of Science, OpenGrey, PubMed, ResearchGate, Cochrane Library, and Google Scholar. These terms were systematically combined using Boolean operators and linked to Parkinsonism. The review prioritized peer-reviewed studies published in the last 10 to 15 years to highlight recent findings, with a few older key studies included. The collected evidence presents a complex picture: the “bystander” hypothesis, which posits that neuronal death triggers Wallerian degeneration and myelin breakdown, is supported; however, multiple lines of evidence also suggest an early, active role for oligodendrocytes. α-synuclein buildup disrupts cellular metabolic support, leading to energy deficits in axons and heightened oxidative stress before neurons are visibly lost. Furthermore, neuroinflammatory responses associated with early demyelination exacerbate the toxic environment, accelerating dopaminergic neuron loss. In conclusion, demyelination is both a consequence and an active contributor to PD progression. Recognizing these dynamics offers new opportunities for therapies that protect myelin, potentially transforming the course of PD.

Graphical abstract
Keywords
Bystander
Demyelination
Myelin
Neurodegeneration
Parkinson’s disease
Remyelination
Funding
None.
Conflict of interest
The authors have no conflict of interest.
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Advanced Neurology, Electronic ISSN: 2810-9619 Print ISSN: 3060-8589, Published by AccScience Publishing
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