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Abstract
Proteinaceous inclusions of aggregated αSynuclein are a hallmark of Parkinson’s Disease. The mechanism by which αSynuclein contributes to pathophysiology through neurotoxicity and through triggering chronic neuroinflammation. While the inciting factor for chronic neuroinflammation is unknown, aggregated αSynuclein has been reported to trigger sterile inflammation in microglia. Aggregated αSynuclein can initiate several pro-inflammatory signaling cascades through many mechanisms including changes in ion currents that alters pro-inflammatory gene expression, induction of DNA damage that activates innate nucleic acid sensors, and through alterations of epitranscriptomic profile. Chronic neuroinflammation is characterized by morphological changes to the resident immune cells of the brain (astrocytes and microglia) and the release of pro-inflammatory cyto/chemokines as well as reactive oxygen and nitrogen species. Biomarker studies have identified the release of pro-inflammatory cyto/chemokines is associated with cognitive decline, increased motor deficits, and poor disease prognosis. Herein, we explored three mechanisms by which αSynuclein may elicit a pro-inflammatory immune response to gain a better understanding of PD etiology. In Chapter 2, we explore how blockade of the potassium channel, Kv1.3, contributes to αSynuclein load in vitro and in vivo. Our cell culture results reveal that Kv1.3 inhibition increases αSynuclein phagocytosis. When translating these findings to rodent models, we observed a trend towards motor deficit rescue and neuroinflammation reduction with Kv1.3 KO. Chapter 3 focuses on how αSynuclein alters the m6A RNA modification landscape through upregulation of ALKBH5 contributes to expression of pro-inflammatory cyto/chemokines. Our findings show that αSynuclein induces upregulation of ALKBH5 as well as modulates ALKBH5 subcellular localization through Fyn-PKCδ mediated phosphorylation. Lastly, Chapter 4 investigates the cytosolic nucleic acid sensor, ZBP1, activates neuroinflammation, as it has been reported to regulate many inflammatory pathways implicated in PD including NLRP3 inflammasome and apoptosis. We demonstrated that αSynuclein induces upregulation of ZBP1 and its binding substrate, Z-nucleic acids. Upregulation of ZBP1 and Z-NA results in activation of necroptotic and apoptotic pathways in microglia. Overall, our findings expand upon the current understandings of microglial response to αSynuclein through epitranscriptomics, nucleic acids sensors, and inhibition of ion channels.