Tissue resident memory CD8+ T cells are present but not critical for demyelination and neurodegeneration in a mouse model of multiple system atrophy.

Multiple system atrophy (MSA) is rare, fast progressing, and fatal synucleinopathy with alpha-synuclein (α-syn) inclusions located within oligodendroglia called glial cytoplasmic inclusions (GCI). Along with GCI pathology there is severe demyelination, neurodegeneration, and neuroinflammation. In post-mortem tissue, there is significant infiltration of CD8+ T cells into the brain parenchyma, however their role in disease progression is unknown. To determine the role of CD8+ T cells, a modified AAV, Olig001-SYN, was used to selectively overexpress α-syn in oligodendrocytes modeling MSA in mice. Four weeks post transduction, we observed significant CD8+ T cell infiltration into the striatum of Olig001-SYN transduced mice recapitulating the CD8+ T cell infiltration observed in post-mortem tissue. To understand the role of CD8+ T cells, a CD8 knockout mice were transduced with Olig001-SYN. Six months post transduction into a mouse lacking CD8+ T cells, demyelination and neurodegeneration were unchanged. Four weeks post transduction, neuroinflammation and demyelination were enhanced in CD8 knockout mice compared to wild type controls. Applying unbiased spectral flow cytometry, CD103+, CD69+, CD44+, CXCR6+, CD8+ T cells were identified when α-syn was present in oligodendrocytes, suggesting the presence of tissue resident memory CD8+ T (Trm) cells during MSA disease progression. This study indicates that CD8+ T cells are not critical in driving MSA pathology but are needed to modulate the neuroinflammation and demyelination response.

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

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.

Disease mechanisms as subtypes: Inflammation in Parkinson disease and related disorders.

Neuroinflammation is a core feature of Parkinson disease (PD) and related disorders. Inflammation is detectable early in PD and persists throughout the disease state. Both the innate and the adaptive arms of the immune system are engaged in both human PD as well as in animal models of the disease. The upstream causes of PD are likely multiple and complex, which makes targeting of disease-modifying therapies based on etiological factors difficult. Inflammation is a broadly shared common mechanism and likely makes an important contribution to progression in most patients with manifest symptoms. Development of treatments targeting neuroinflammation in PD will require an understanding of the specific immune mechanisms which are active, their relative effects on both injury and neurorestoration, as well as the role of key variables likely to modulate the immune response: age, sex, the nature of the proteinopathies present, and the presence of copathologies. Studies characterizing the specific state of immune response in individuals and groups of people affected by PD will be essential to the development of targeted disease-modifying immunotherapies.