The Activation of LRRK2 by Alpha-Synuclein

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DESCRIPTION (provided by applicant): Autosomal dominant mutations in LRRK2 are the most common genetic cause of Parkinson's disease (PD). Notably, LRRK2-associated PD is clinically indistinguishable from idiopathic PD, and generally is accompanied by the presence of the classic intracellular inclusions of a-synuclein called Lewy bodies, the pathological hallmark of PD. However, identifying biochemical links between a-synuclein aggregation and LRRK2 function has proven difficult. Prior work may have been thwarted by the assumption that the common pathways involving these two disease-linked proteins must occur within the same cell. Recent evidence demonstrates the expression and potent regulation of LRRK2 in non-neuronal cells including microglia, particularly during neuroinflammation. �ynuclein, on the other hand, is exclusively expressed by neurons in the brain but is secreted by a yet unidentified mechanism. Recent data from multiple labs suggest that extracellular a-synuclein can serve as a ligand to activate microglial cells, which express LRRK2. In this application we will screen primary cultured murine microglia for the effects of multiple conformations and assemblies of a- synuclein, identifying those that activate microglial LRRK2, and confirm these effects in cultured human microglia. Next, using two distinct knock-in mouse models expressing endogenous levels of mutant LRRK2 (R1441C and G2019S), we will determine how pathogenic mutations in LRRK2 alter the a-synuclein- dependent microglial responses, both in vitro and in vivo. This will involve an analysis of how pathogenic LRRK2 mutations influence microglial responses to pathogenic a-synuclein exposure probing important biochemical properties of the LRRK2 protein and the effects on microglial behavior and function. This exploratory project will test a novel hypothesis regarding the functional interactions between LRRK2 and a- synuclein, and may add valuable insight into potential pathways integrating what are arguably the two most important PD-linked gene products.