Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble α‐synuclein
Abstract
Recently, α‐synuclein was shown to be a structural component of the filaments in Lewy bodies (LBs) of Parkinson's disease (PD), dementia with LBs (DLB) as well as the LB variant of Alzheimer's disease, and this suggests that α‐synuclein could play a mechanistic role in the pathogenesis of these disorders. To determine whether α‐synuclein is a building block of inclusions in other neurodegenerative movement disorders, we examined brains from patients with multiple system atrophy (MSA) and detected α‐synuclein, but not β‐ or γ‐synuclein, in glial cytoplasmic inclusions (GCIs) throughout the MSA brain. In MSA white matter, α‐synuclein–positive GCIs were restricted to oligodendrocytes, and α‐synuclein accumulated selectively in MSA white matter with α‐synuclein–positive GCIs. Taken together with evidence that LBs contain insoluble α‐synuclein, our data suggest that a reduction in the solubility of α‐synuclein may induce this protein to form filaments that aggregate into cytoplasmic inclusions, which contribute to the dysfunction or death of glial cells as well as neurons in neurodegenerative disorders with different phenotypes.
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MSA is characterized neuropathologically by α-syn-positive glial cytoplasmic inclusions (GCIs) in oligodendroglia.
“MSA is a synucleinopathy, however, unlike PD and dementia with Lewy bodies, in which α-syn accumulates and aggregates in neurons, MSA is characterized neuropathologically by α-syn-positive glial cytoplasmic inclusions (GCIs) in oligodendroglia [1, 42, 54, 58, 59].”
From Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates (2017) · cites this paper as [54]
The pathological hallmark of MSA is abnormal accumulation of α-syn in the cytoplasm of oligodendrocytes, named glial cytoplasmic inclusions (GCIs).
“The pathological hallmark of MSA is the abnormal accumulation of α-syn in the cytoplasm of oligodendrocytes, named glial cytoplasmic inclusions (GCIs).271–275”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [272]
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Human Astrocytes Transfer Aggregated Alpha-Synuclein via Tunneling Nanotubes
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Self-citationBiophysics of Parkinsons Disease: Structure and Aggregation of α- Synuclein
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Self-citationα-Synuclein pathology in Parkinson’s disease and related α-synucleinopathies
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Functional Consequences of α-Synuclein Tyrosine Nitration
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Self-citationMutation E46K increases phospholipid binding and assembly into filaments of human α‐synuclein
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Widespread Nitration of Pathological Inclusions in Neurodegenerative Synucleinopathies
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Self-citationAlpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo
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Molecular mechanisms of α-synuclein neurodegeneration
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Self-citationα-Synuclein Overexpression Protects against Paraquat-Induced Neurodegeneration
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α-Synuclein: Normal Function and Role in Neurodegenerative Diseases
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Self-citation
- Authors
- Tu, P., Galvin, J. E., Baba, M., Giasson, B., Tomita, T., Leight, S., Nakajo, S., Iwatsubo, T., Trojanowski, J. Q., & Lee, V. M. ‐.
- Affiliations
- University of Pennsylvania (US)
- The University of Tokyo (JP)
- SHOWA Medical University (JP)
- Corresponding author
- Lee, Virginia M.‐Y.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 1998-09
- Volume
- 44
- Issue
- 3
- Pages
- 415-422
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2133068803
- Cited by
- 686
- References
- 43
- Citations by year
- 2026: 14 · 2025: 21 · 2024: 33 · 2023: 23 · 2022: 25 · 2021: 28 · 2020: 21 · 2019: 24 · 2018: 21 · 2017: 23 · 2016: 12 · 2015: 20 · 2014: 24 · 2013: 18 · 2012: 17
- FWCI
- 30.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH.NS 31862)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- alpha-synuclein, glial cytoplasmic inclusions, multiple system atrophy, oligodendrocytes, white matter, Lewy bodies, protein aggregation, neurodegenerative movement disorders, immunoelectron microscopy, synuclein
- MeSH terms
- Adult, Aged, Aged, 80 and over, Antibodies, Inclusion Bodies, Female, Humans, Male, Actin Cytoskeleton, Middle Aged, Myelin Sheath, Nerve Tissue Proteins, Neuroglia, Oligodendroglia, Solubility, Multiple System Atrophy, Synucleins, alpha-Synuclein, gamma-Synuclein
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