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.

Public Health Relevance

Lewy body dementia and its related spectrum of neurodegenerative disorders are characterized by the progressive accumulation of ?-synuclein inclusions in the nervous system. Recent findings from many laboratories, including ours, show that ?-synuclein pathology may spread in the brain, perhaps even from the peripheral nervous system, by a prion- like mechanism. Our preliminary data suggests that activation of peripheral immunity may play a role in exacerbating the prionoid properties of ?-synuclein. To test this hypothesis, we have devised experiments that will allow us to investigate whether activating cellular immunity prior to peripheral challenge with exogenous ?-synuclein exacerbates prionoid properties of ?-synuclein and conversely to explore whether prionoid properties of ?-synuclein will be suppressed in mice lacking a functional immune system. These findings will provide pivotal information regarding the interplay between prionoid properties of ?-synuclein, cellular immunity and neuronal death and throw light on the mechanism of disease pathogenesis in Parkinson's disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Sutherland, Margaret L
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University of Florida
Schools of Medicine
United States
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Sorrentino, Zachary A; Xia, Yuxing; Funk, Cory et al. (2018) Motor neuron loss and neuroinflammation in a model of ?-synuclein-induced neurodegeneration. Neurobiol Dis 120:98-106