Oligodendroglial α‐synucleinopathy‐driven neuroinflammation in multiple system atrophy
Open accessAbstract
Neuroinflammation and oligodendroglial cytoplasmic α‐synuclein (α‐syn) inclusions (GCIs) are important neuropathological characteristics of multiple system atrophy (MSA). GCIs are known to interfere with oligodendroglial maturation and consequently result in myelin loss. The neuroinflammatory phenotype in the context of MSA, however, remains poorly understood. Here, we demonstrate MSA‐associated neuroinflammation being restricted to myeloid cells and tightly linked to oligodendroglial α‐syncleinopathy. In human putaminal post‐mortem tissue of MSA patients, neuroinflammation was observed in white matter regions only. This locally restricted neuroinflammation coincided with elevated numbers of α‐syn inclusions, while gray matter with less α‐synucleinopathy remained unaffected. In order to analyze the temporal pattern of neuroinflammation, a transgenic mouse model overexpressing human α‐syn under the control of an oligodendrocyte‐specific myelin basic protein (MBP) promoter (MBP29‐hα‐syn mice) was assessed in a pre‐symptomatic and symptomatic disease stage. Strikingly, we detected an increased neuroinflammation in regions with a high α‐syn load, the corpus callosum and the striatum, of MBP29‐hα‐syn mice, already at a pre‐symptomatic stage. Furthermore, this inflammatory response was restricted to myeloid cells being highly proliferative and showing an activated, phagocytic phenotype. In contrast, severe astrogliosis was observed only in gray matter regions of MSA patients as well as MBP29‐hα‐syn mice. To further characterize the influence of oligodendrocytes on initiation of the myeloid immune response, we performed RNA sequencing analysis of α‐syn overexpressing primary oligodendrocytes. A distinct gene expression profile including upregulation of cytokines important for myeloid cell attraction and proliferation was detected in α‐syn overexpressing oligodendrocytes. Additionally, microdissected tissue of MBP29‐hα‐syn mice exhibited a similar cellular gene expression profile in white matter regions even pre‐symptomatically. Collectively, these results imply an early crosstalk between neuroinflammation and oligodendrocytes containing α‐syn inclusions leading to an immune response locally restricted to white matter regions in MSA.
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Histopathological studies showed that microglial activation increased in regions with a high α-syn load in MSA patients.
“Histopathological studies showed that microglial activation increased in regions with a high α-syn load in MSA patients.291”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [291]
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Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets
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- Authors
- Hoffmann, A., Ettle, B., Battis, K., Reiprich, S., Schlachetzki, J. C. M., Masliah, E., Wegner, M., Kuhlmann, T., Riemenschneider, M. J., & Winkler, J.
- Affiliations
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- National Institutes of Health (US)
- University Hospital Münster (DE)
- University Hospital Regensburg (DE)
- Corresponding author
- Winkler, Jürgen
- ORCID
- Venue
- Brain Pathology
- Publisher
- Wiley
- Published
- 2019-01-31
- Volume
- 29
- Issue
- 3
- Pages
- 380-396
- ISSN
- 1015-6305 (ISSN-L)
- 1750-3639
- PMC
- PMC6850330
- OpenAlex
- W2901746027
- Cited by
- 83
- References
- 93
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 21 · 2023: 15 · 2022: 11 · 2021: 9 · 2020: 12 · 2019: 3
- FWCI
- 4.07
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain Pathology (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SCHL 21021‐1, INST 410/45‐1 FUGG, DFG GRK2162)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- multiple system atrophy, neuroinflammation, alpha-synuclein, glial cytoplasmic inclusions, myeloid cells, oligodendrocytes, demyelination, astrocyte activation, white matter, transgenic mouse model, myelin basic protein promoter, cytokines, corpus callosum, striatum
- MeSH terms
- Synucleinopathies, Aged, Animals, Brain, Inclusion Bodies, Corpus Striatum, Disease Models, Animal, Female, Humans, Male, Mice, Transgenic, Middle Aged, Neurons, Oligodendroglia, Neuroimmunomodulation, Multiple System Atrophy, Myeloid Cells, Mice, alpha-Synuclein, White Matter
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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