This proposal is a renewal of our current VA Merit award and is focused on understanding the interactions between innate immune responses and Parkinson’s Disease (PD) pathogenesis. We previously discovered that the neuronal protein, alpha-synuclein (α-syn), protects the brain from viral infections. With our current VA Merit support, we extended these findings to discover that α-syn expression in neurons is required for expression of neuronal interferon stimulated gene (ISG) expression independent of microglial activation during acute viral infection in the brain. Loss of neuron-specific expression of α-syn results in increased virus growth in primary human neurons and decreased activation of infiltrating cytotoxic T-cell responses. We extended these findings to show that stimulation of specific RNA sensing and signaling pathways within neurons activates ISGs in an α-syn-dependent mechanism. Our current mechanistic studies form the foundation for the current proposal. For the next phase of our work and the subject of the current VA merit award application, we want to understand the role of α-syn-dependent innate immune responses in progression of PD neuropathology. Our fundamental hypothesis is that PD is an innate immune disorder and that inhibition of specific innate immune pathways associated with α-syn-dependent innate immune responses will inhibit the progression of PD pathology. The Brundin laboratory, our collaborator, has developed a murine model of prodromal PD that recapitulates the spread of α-syn pathology from the olfactory bulb to the midbrain in mice. This proposal combines this disease relevant model with approaches for targeted knockout or stimulation of specific innate immune responses to determine the effect on propagation of α-syn pathology, neurodegeneration, and inflammatory responses in the brain. The three independent, related aims will provide novel insight into a potential disease-modifying therapeutic intervention for PD. The first aim will use target gene knockout of specific innate immune genes to determine the role of specific innate immune pathways on the progression of PD pathology. The second aim will use targeted stimulation of select innate immune pathways and evaluate the effect on PD pathology. The third aim will employ inhibitory antibodies for specific innate immune pathways and determine the role of antibody-mediated inhibition of selected innate immune pathways on the progression of PD pathology. If the studies are completed as outlined, we will identify potential disease modifying targets for the treatment of PD.

Parkinson’s disease (PD) results from progressive neurodegeneration in the central nervous system. The neuronal protein, alpha-synuclein, forms fibrils within neurons that can then spread to other neurons resulting in the progressive pathology noted in PD patients. Recently, our data and others have shown that the alpha- synuclein protein acts as an innate immune signaling molecule within neurons. This application will study focused inhibition and stimulation of select innate immune signaling pathways in the brain in the progression of PD pathology using a well-established mouse model of prodromal PD. If the proposed work is completed as outlined, this work will identify potential disease-modifying targets for the treatment of PD.