MSA is a progressive neurodegenerative disorder caused by the accumulation and aggregation of misfolded forms of the protein alpha-synuclein (α-syn) in oligodendrogila. In addition to neurodegeneration, demyelination, and autonomic dysfunction, recent work has highlighted a key role for the immune system in the pathophysiology of disease. In postmortem MSA brains, we found α-syn pathology is accompanied by HLA-DR+ (MHCII) reactive microglia, increased pro-inflammatory cytokine expression, and infiltration of peripheral lymphocytes. While inflammation has been reported in human disease and in animal models, it is currently unknown specifically what immune-mediated mechanisms are critical to disease pathogenesis and whether targeting those mechanisms are protective. Utilizing a novel viral vector that selectively targets oligos (Olig001-SYN) in mice, my lab found that α- syn overexpression in oligodendrocytes induces robust neuroinflammation similar to that seen in MSA patients. To determine if the adaptive immune system plays a disease driving role in MSA pathology, we genetically and pharmacologically inhibited CD4+ T cell infiltration and effector function in mice transduced with Olig001-SYN. We found that modulating T-cell trafficking and cytokine expression attenuated neuroinflammation and demyelination in the CNS, suggesting antigen-specific T cell responses are required for disease. These results indicate that targeting the immune system in MSA is disease modifying, at least in model systems, and represents a promising avenue for therapeutic intervention. A critical next step is identifying cell-specific pathways for potential disease interventions. The overall goal of the work proposed in this renewal application is to utilize genetic, and discovery-based approaches to isolate and selectively target disease driving immune pathways in a preclinical model of MSA. Given the role of CD4 T cells in many immune processes including microglial activation, cytokine responses in the CNS, and B cell maturation, it is important to determine the mechanisms and timing of CD4 T cell activation and the nature of the underlying antigens that are specifically active in MSA. CD4 T cell activation is likely to involve CNS resident macrophages, which are important for recruiting CD4 T cells to the CNS, and to engage downstream B cell effector functions. Based on this, we will test the hypothesis that abnormal α-syn expression in oligodendrocytes drives enhanced adaptive immune responses through activation of CNS resident macrophages (Aim 1), and that this activation leads to antigen specific T (Aim 2) and B cell responses (Aim 3) resulting in harmful neuroinflammation, demyelination, and neurodegeneration in MSA. Currently there are no available therapies that slow or halt disease progression. Long term, we hope the results from these research studies will show where to target disease-modifying therapies in the pre-clinical space and will also be important f...