Immune modulation and CNS pathology following exogenous ?-synuclein challenge

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Progressive accumulation of intracellular inclusions of α-synuclein protein in the nervous system is a characteristic feature of Lewy Body diseases which is part of a spectrum of sporadic and hereditary neurodegenerative diseases termed α- synucleinopathies. The definitive involvement of α-synuclein in the etiology of these disorders was established by the findings that mutations in α-synuclein can directly cause Lewy body dementia. Many studies suggest that the progressive spread of α-synuclein pathology in the peripheral nervous system and the brain occurs through direct α-synuclein transmission between cells. However, there is a major gap in our understanding of the epigenetic factors that modulate such prionoid properties of α-synuclein. Our preliminary data suggests that α-synuclein is an immunogenic protein and that additional factors, such as activation of cellular immunity, may contribute to the prionoid propagation of peripherally administered exogenous α-synuclein to the CNS of mice. To provide novel insights into immune-mediated mechanisms involved in induction of CNS α-synuclein inclusion pathology following peripheral challenge with exogenous α-synuclein, we have assembled a team of experienced investigators with diverse and unique expertise in α-synuclein proteostasis and neuroimmune regulation. In Aim 1, we will determine whether inflammatory preconditioning of peripheral immune milieu exacerbates induction and CNS transmission of α-synuclein pathology following peripheral challenge with exogenous α- synuclein fibrils. In Aim 2, we will test whether the prionoid properties of α-synuclein fibrils is suppressed in two independent lines of immunodeficient α-synuclein transgenic mice. Our study will inform us on the interplay between α- synuclein seeding and propagation and cellular immunity. We expect our study to be highly translational as it will clarify 1) potential interactions between α-synuclein and cellular immunity and further help us 2) devise preventive immunobiotherapies strategies to slow down intercellular α-synuclein pathogenesis in the future.