Mechanisms of alpha-synuclein mediated inflammation in multiple system atrophy

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Project Summary/Abstract 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 and autonomic dysfunction, recent work has highlighted a key role for the immune system in the pathophysiology of disease. In postmortem brains, α-syn pathology is accompanied by HLA-DR+ (MHCII) reactive microgliosis, 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 overexpresses α-syn in oligodendrocytes (Olig001-SYN), I have obtained preliminary data showing a robust inflammatory response including MHCII+ expression on resident microglia and infiltrating monocytes, and entry of T cells closely modeling what has been reported in human disease. In this proposal, I will use this newly developed Olig001-SYN model of MSA in combination with transgenic mice and technologies to dissect the mechanisms of α-syn-related toxicity. Specifically, I will dissect the role of central nervous system (CNS) resident microglia in initiating the immune response by presenting antigen via MHCII to CNS patrolling CD4+ T cells, and the role of infiltrating monocytes and CD4 T cells in mediating demyelination and neurodegeneration. Microglia act as the resident immune cells of the brain, and are the first to respond to neural insult. In the first aim of this proposal, I will determine whether deletion of MHCII from CNS resident microglia is protective against α-syn-induced monocyte and T cell invasion, inflammation, demyelination, and neurodegeneration. In aims 2 and 3, I will determine whether blocking peripheral immune cell infiltrate using genetic deletion and pharmacological inhibitors attenuates inflammation, demyelination, and neurodegeneration observed in the Olig001-SYN model of MSA. Currently there are no available therapies that slow or halt disease progression. Long term, I 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 for studying immune responses in other synucleinopathy disease models including Parkinson disease, dementia with Lewy bodies, and atypical Parkinsonisms.