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Published in: Acta Neuropathologica Communications 1/2024

Open Access 01-12-2024 | Interferon | Research

IFNγ drives neuroinflammation, demyelination, and neurodegeneration in a mouse model of multiple system atrophy

Authors: Nicole J. Corbin-Stein, Gabrielle M. Childers, Jhodi M. Webster, Asta Zane, Ya-Ting Yang, Nikhita Mudium, Rajesh Gupta, Fredric P. Manfredsson, Jeffrey H. Kordower, Ashley S. Harms

Published in: Acta Neuropathologica Communications | Issue 1/2024

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Abstract

Multiple system atrophy (MSA) is a rare and fatal synucleinopathy characterized by insoluble alpha-synuclein (α-syn) cytoplasmic inclusions located within oligodendroglia. Neuroinflammation, demyelination, and neurodegeneration are correlated with areas of glia cytoplasmic inclusions (GCI) pathology, however it is not known what specifically drives disease pathogenesis. Recent studies have shown that disease pathologies found in post-mortem tissue from MSA patients can be modeled in rodents via a modified AAV overexpressing α-syn, Olig001-SYN, which has a 95% tropism for oligodendrocytes. In the Olig001-SYN mouse model, CD4+ T cells have been shown to drive neuroinflammation and demyelination, however the mechanism by which this occurs remains unclear. In this study we use genetic and pharmacological approaches in the Olig001-SYN model of MSA to show that the pro-inflammatory cytokine interferon gamma (IFNγ) drives neuroinflammation, demyelination, and neurodegeneration. Furthermore, using an IFNγ reporter mouse, we found that infiltrating CD4+ T cells were the primary producers of IFNγ in response to α-syn overexpression in oligodendrocytes. Results from these studies indicate that IFNγ expression from CD4+ T cells drives α-syn-mediated neuroinflammation, demyelination, and neurodegeneration. These results indicate that targeting IFNγ expression may be a potential disease modifying therapeutic strategy for MSA.
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Metadata
Title
IFNγ drives neuroinflammation, demyelination, and neurodegeneration in a mouse model of multiple system atrophy
Authors
Nicole J. Corbin-Stein
Gabrielle M. Childers
Jhodi M. Webster
Asta Zane
Ya-Ting Yang
Nikhita Mudium
Rajesh Gupta
Fredric P. Manfredsson
Jeffrey H. Kordower
Ashley S. Harms
Publication date
01-12-2024
Publisher
BioMed Central
Keyword
Interferon
Published in
Acta Neuropathologica Communications / Issue 1/2024
Electronic ISSN: 2051-5960
DOI
https://doi.org/10.1186/s40478-023-01710-x

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