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isk patients. ClinicalTrials.gov , NCT04341974 . ClinicalTrials.gov , NCT04341974 . Mutations in LRRK2 are the most common cause of familial Parkinson's disease and typically cause disease in the context of abnormal aggregation and deposition of α-synuclein within affected brain tissue. We combine genetic analysis of Lrrk-associated toxicity in a penetrant Drosophila model of wild type human α-synuclein neurotoxicity with biochemical analyses and modeling of LRRK2 toxicity in human neurons and transgenic mouse models. We demonstrate