IFNγ drives neuroinflammation, demyelination, and neurodegeneration in a mouse model of multiple system atrophy.
Document Type
Article
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.
Keywords
Animals, Humans, Mice, alpha-Synuclein, Demyelinating Diseases, Disease Models, Animal, Interferon-gamma, Multiple System Atrophy, Neuroinflammatory Diseases, Oligodendroglia, Synucleinopathies
Medical Subject Headings
Animals; Humans; Mice; alpha-Synuclein; Demyelinating Diseases; Disease Models, Animal; Interferon-gamma; Multiple System Atrophy; Neuroinflammatory Diseases; Oligodendroglia; Synucleinopathies
Publication Date
1-18-2024
Publication Title
Acta Neuropathol Commun
ISSN
2051-5960
Volume
12
Issue
1
First Page
11
Last Page
11
PubMed ID
38238869
Digital Object Identifier (DOI)
10.1186/s40478-023-01710-x
Recommended Citation
Corbin-Stein, Nicole J; Childers, Gabrielle M; Webster, Jhodi M; Zane, Asta; Yang, Ya-Ting; Mudium, Nikhita; Gupta, Rajesh; Manfredsson, Fredric P.; Kordower, Jeffrey H; and Harms, Ashley S, "IFNγ drives neuroinflammation, demyelination, and neurodegeneration in a mouse model of multiple system atrophy." (2024). Translational Neuroscience. 2383.
https://scholar.barrowneuro.org/neurobiology/2383