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.
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.
|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|