Exosomes and Neuroinflammation in Parkinsons Disease

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DESCRIPTION (provided by applicant): Neuroinflammation has been implicated as a major pathophysiological process of Parkinson's disease (PD) in recent years. Among various neuroinflammatory triggers, protein aggregates have been shown to be a predominant pathological trigger for microglial activation and subsequent proinflammatory cytokine and chemokine production in the brain, which in turn con tributes to the accelerated progression of neurodegenerative processes. Also, emerging evidence indicates that aggregated pathogenic proteins, including α-synuclein (αSyn), are packaged into exosomes, which propagate protein aggregates from affected neurons to other brain cells, including microglial cells, through a non-cellular autonomous process, leading to a heightened neuroinflammatory response. Despite these advances, the cellular mechanisms underlying microglia-mediated neuroinflammatory events following stimulation with αSyn aggregates and αSyn-containing exosomes are yet to be defined. While studying kinase signaling in PD models, we unexpectedly discovered that the major non-receptor tyrosine kinase Fyn is rapidly activated in primary microglia within a few minutes of stimulation with the known inflammogen LPS. Interestingly, Fyn activation triggers proinflammatory responses, including cytokine/chemokine release from microglia. In addition, our preliminary findings revealed that aggregated αSyn also induced a rapid activation of Fyn kinase and the NLRP3 inflammasome. To further expand our novel preliminary results, we will systematically pursue the following specific aims: (i) to characterize the mechanism of Fyn kinase activation and its role in the regulation of NLRRP2/3 inflammasomes in microglia and astrocytes during inflammatory stress induced by αSyn aggregates and exosomes containing αSyn aggregates and to determine the proinflammatory role of Fyn in dopaminergic neuronal cell death, (ii) to define the molecular mechanisms underlying Fyn upregulation in microglia and astroglia during sustained inflammatory responses induced by αSyn aggregates and αSyn exosomes in animal models of PD, and (iii) to determine the role of Fyn in mediating the proinflammatory response in the nigrostriatal dopaminergic system during αSyn protein aggregation in animal models of PD as well as in postmortem PD brain tissues. Biochemical, cellular and neurochemical approaches will be used to achieve these specific aims. Taken together, delineating the role of Fyn kinase in αSyn protein aggregation-induced microglial activation will not only provide novel mechanistic insights into the progression of neurodegenerative processes in PD, but may also be useful for translating mechanistic outcomes into effective therapies for PD.