Immune modulation and CNS pathology following exogenous ?-synuclein challenge

University Of Florida, Gainesville FL

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Abstract

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