Cited by 686Parkinson's Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration MechanismsNuclear Receptors and Signaling

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Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble α‐synuclein

Tu, Pang‐hsien, Galvin, James E., Baba, Minami, Giasson, Benoit, Tomita, Taisuke, Leight, Susan, Nakajo, Shigeo, Iwatsubo, Takeshi, Trojanowski, John Q., Lee, Virginia M.‐Y.·1998·Annals of Neurology

DOI 10.1002/ana.410440324

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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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Background
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Ross, O. A., Awayn, N. H., McWhinney, D., Maxwell, L. D., El‐Agnaf, O. M. A., Barnett, Y., Rea, I. M., Middleton, D., Wallace, A., Gibson, J. M., et al. (2002) · Neuroreport · doi:10.1097/00001756-200209160-00010 · Cited by 4
Untitled work
Solano (2000) · doi:10.1002/1531-8249(200002)47:2 · Cited by 3
Transcriptional dysregulation in the cerebellum triggered by oligodendroglial α-synucleinopathy: insights from a transgenic mouse into the early disease mechanisms of MSA
Heras‐Garvin, A., Fellner, L., Granata, R., Wenning, G. K., & Stefanova, N. (2025) · Journal of Neural Transmission · doi:10.1007/s00702-025-02892-5 · Cited by 3
“…inclusions (GCIs), the histopathological hallmark of MSA (Fanciulli and Wenning 2015; Spillan - tini et al. 1997 ; Trojanowski and Lee 2003; Tu et al. 1998 ). α-syn accumulation in MSA leads to glial and neuronal dysfunction, neuroinflammation and finally neurodegeneration (Fanciulli and…”
Plasma matrix metalloproteinase-3 correlates with the clinical severity in men with multiple system atrophy
Sasaki, H., Matsushima, M., Hama, Y., Sakushima, K., Nakamura, M., Yabe, I., Oba, K., Tanji, K., Mori, F., Wakabayashi, K., et al. (2013) · Neurology and Clinical Neuroscience · doi:10.1002/ncn3.22 · Cited by 3
Multiple System Atrophy
Heras‐Garvin, A., & Stefanova, N. (2022) · Springer eBooks · doi:10.1007/978-3-031-15080-7_228 · Cited by 3
Conjugal Synucleinopathies: A Clinicopathologic Study
Adler, C. H., Halverson, M., Zhang, N., Shill, H. A., Driver‐Dunckley, E. D., Mehta, S. H., Atri, A., Caviness, J. N., Serrano, G. E., Shprecher, D., et al. (2024) · Movement Disorders · doi:10.1002/mds.29783 · Cited by 3
Eye Movement Disorders
Gold, D. R. (2018) · Elsevier eBooks · doi:10.1016/b978-0-323-34044-1.00016-x · Cited by 3
Parkinsonism-Plus Syndromes and Secondary Parkinsonian Disorders
Fahn, S., Jankovic, J. J., Hallett, M., & Jenner, P. G. (2007) · Elsevier eBooks · doi:10.1016/b978-0-443-07941-2.50013-9 · Cited by 3
Aetiopathogenesis
Jellinger, K. A., & Krismer, F. (2013) · Springer eBooks · doi:10.1007/978-3-7091-0687-7_4 · Cited by 3
Autophagy–Lysosome Pathway in Multiple System Atrophy Pathogenesis: The Best Is Yet to Come
Mavroeidi, P., & Xilouri, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262010204 · Cited by 2
“…with the oligodendroglial-specific phosphoprotein tubulin-polymerization promoting protein TPPP/p25 α [5], deposit mostly within the cytoplasm of oligodendrocytes, the myelinating cells of the central nervous system (CNS), leading to the composition of glial cytoplasmic inclusions (GCIs) [6,7].”
Skin-derived α-synuclein strains from PD, DLB, and MSA induce distinct intracellular pathology and neurodegeneration
Raina, A., Wang, W., Gonzalez, J., Yan, X. E., Overstreet‐Wadiche, L., Wadiche, J. I., Zhang, C., & Chen, S. G. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.111005 · Cited by 3
“…of misfolded and aggregated alpha-synuclein ( α Syn) in the brain is a pathological hallmark of a group of neurodegenerative diseases collectively called synu-cleinopathies, which include Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) (1–5).”
Multiple system atrophy
Granata, R., & Wenning, G. K. (2011) · Cambridge University Press eBooks · doi:10.1017/cbo9780511920936.004 · Cited by 2
Atypical parkinsonism, parkinsonism-plus syndromes and secondary parkinsonian disorders
Jankovic, J. J., Hallett, M., Okun, M. S., Comella, C., Fahn, S., & Goldman, J. G. (2021) · Elsevier eBooks · doi:10.1016/b978-0-323-31071-0.00009-3 · Cited by 2
Plasma α-synuclein domain profiles across α-synucleinopathies
Pons, M., Mohaupt, P., Vialaret, J., Mondésert, E., Vignon, M., Coppens, S., Stéphane, M., Lehmann, S., & Hirtz, C. (2025) · Brain Communications · doi:10.1093/braincomms/fcaf189 · Cited by 2
“5 The differential diagnosis among these disorders is hampered by overlapping clinical symptoms, particularly in the early stages of Parkinson’s disease and MSA.”
Exidavnemab binds to aggregated α-synuclein in human brains affected by α-synucleinopathies
Zachrisson, O., Johannesson, M., Söderberg, L., Eriksson, F., Sunnemark, D., Nordström, E. K. L., Björklund, M., Button, E. B., Odergren, T., Möller, C., et al. (2025) · Neurotherapeutics · doi:10.1016/j.neurot.2025.e00779 · Cited by 2
“The neuropathology of MSA is also characterized by the progressive accumulation of aggregated α -synuclein [13].”
β-synuclein protein from Xenopus laevis: Overexpression in Escherichia coli of the GST-tagged protein and production of polyclonal antibodies
Yuan, Z., Zhao, X., Yan, F., Zhao, J., Liu, H., Xiong, S., Li, J., Chen, L., & Wei, Y. (2007) · Biochemistry (Moscow) · doi:10.1134/s0006297907110144 · Cited by 2
Upregulation of α-synuclein expression in the rat cerebellum in experimental hepatic encephalopathy
Suárez, I., Bodega, G., & Fernández, B. (2010) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2010.01083.x · Cited by 2
Detection of Aggregates and Protein Inclusions by Staining of Tissues
Galvin, J. E. (2003) · Humana Press eBooks · doi:10.1385/1-59259-394-1:149 · Cited by 2
Self-citation
Atypical parkinsonism, parkinsonism-plus syndromes, and secondary parkinsonian disorders
Fahn, S., Jankovic, J. J., & Hallett, M. (2011) · Elsevier eBooks · doi:10.1016/b978-1-4377-2369-4.00009-3 · Cited by 2
Autonomic dysfunction
Mathias, C. J., & Freeman, R. L. (2003) · Elsevier eBooks · doi:10.1016/b978-012125831-3/50298-7 · Cited by 2
Tissue resident memory CD8+ T cells are present but not critical for demyelination and neurodegeneration in a mouse model of multiple system atrophyPreprint
Corbin-Stein, N. J., Childers, G. M., Webster, J. M., Zane, A., Yang, Y., Ali, M. A., Sandoval, I. M., Manfredsson, F. P., Kordower, J. H., Tyrrell, D. J., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.02.597035 · Cited by 3
“MSA is classified as a synucleinopathy due to the presence of alpha synuclein (α-syn) in insoluble glia cytoplasmic inclusions (GCIs) located predominantly in oligodendrocytes[8, 25, 28, 34, 37].”
Background
Comparing alpha-synuclein-interactomes between multiple systems atrophy and Parkinson’s disease reveals unique and shared pathological featuresPreprint
Choi, S. G., Tittle, T., Barot, R., Betts, D., Gallagher, J. J., Kordower, J. H., Chu, Y., & Killinger, B. A. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.20.613717 · Cited by 2
“In contrast, MSA cases had widespread PSER129 pathology in the white matter tracts of the midbrain and forebrain, consistent with known white matter involvement for MSA 15,16 (Fig.”
Result
Etiology, Pathology, and Pathogenesis
Geser, F., Jellinger, K. A., Köllensperger, M., Stefanova, N., & Wenning, G. K. (2009) · Blue books of neurology · doi:10.1016/b978-1-4160-6641-5.00019-2 · Cited by 2
α-Synuclein-Assembled Synaptic Vesicle Pools at the Presynaptic Terminal: A Study of α-Synuclein Function Using a Novel Mouse Model
Suzuki, C., Yamaguchi, J., Tanida, I., & Uchiyama, Y. (2025) · ACTA HISTOCHEMICA ET CYTOCHEMICA · doi:10.1267/ahc.25-00017 · Cited by 1
Protein-First, but Not Protein-Only: Rethinking Neurodegenerative Diseases Through Transgenic Mouse Models
Zeng, C. (2026) · Neurology International · doi:10.3390/neurolint18070139 · Cited by 1
“Multiple system atrophy is another α -synucleinopathy, but it differs from PD and dementia with Lewy bodies because α Syn accumulates prominently in oligodendrocytes as glial cytoplasmic inclusions [9,10].”
Influential
Pathogenesis of neurodegenerative diseases via templated recruitment
Guo, J. (2013) · ScholarlyCommons (University of Pennsylvania) · Cited by 1
Neuropathology of Ataxias
Yamada, M. (2021) · Springer eBooks · doi:10.1007/978-3-030-23810-0_104 · Cited by 1
Role of Astrocyte Dysfunction in Parkinson’s Disease Pathogenesis
Datta, I., Raj, A., & Kaushal, A. (2022) · Springer eBooks · doi:10.1007/978-981-16-8313-8_10 · Cited by 2
Highlights in clinical autonomic neurosciences: Clinical update on multiple system atrophy
Cheshire, W. P. (2014) · Autonomic Neuroscience · doi:10.1016/j.autneu.2014.08.005 · Cited by 1
“Oligodendroglial cytoplasmic inclusions containing aggregates of misfoldedα-synuclein constitute the pathological hallmark of MSA (Tu et al., 1998; Wakabayashi et al., 1998).”
α-Synuclein, synphilin-1 and inclusion body formation in α-synucleinopathies
Wakabayashi, K., & Takahashi, H. (2003) · International Congress Series · doi:10.1016/s0531-5131(03)00115-8 · Cited by 1
Neurodegenerative α-Synucleinopathies
Goedert, M., & Spillantini, M. G. (2005) · Humana Press eBooks · doi:10.1385/1-59259-834-x:077 · Cited by 1
“The Lewy body pathology that is sometimes associated with other neurodegenerative diseases, such as Alzheimer’s disease, the parkinsonism-dementia complex of Guam, and neurodegeneration with brain iron accumulation type I has also been shown to be immunoreactive for α-synuclein (7,63,64).”
Background
Tau and α-Synuclein in Neurodegenerative Diseases
Giasson, B. I., Wilson, C., Trojanowski, J. Q., & Lee, V. M. ‐. (2001) · Humana Press eBooks · doi:10.1007/978-1-59259-006-3_7 · Cited by 1
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: Tu, Pang‐hsien
Galvin, James E.
Giasson, Benoit
Tomita, Taisuke
Iwatsubo, Takeshi
Trojanowski, John Q.
Lee, Virginia M.‐Y.
Venue: Annals of Neurology
Publisher: Wiley
Published: 1998-09
Volume: 44
Issue: 3
Pages: 415-422
ISSN: 0364-5134 (ISSN-L)
1531-8249
DOI: 10.1002/ana.410440324
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
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 2229 d)
Locations: Annals of Neurology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Mental Health (MH.NS 31862)
Topics: Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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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Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble α‐synuclein

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