Project Summary/Abstract
MSA is a progressive neurodegenerative disorder caused by the accumulation and aggregation of
misfolded forms of the protein alpha-synuclein (a-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, a-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 a-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 a-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 a-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.