Neurodegenerative dementias, such as Alzheimer's disease (AD), frontotemporal lobar degeneration, and Lewy body dementia, are caused by abnormalities in proteostasis and accumulation of misfolded prion-like proteins in the brain. Mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene result in diverse neuropathology, including tauopathy, synucleinopathy, TDP-43 proteinopathy, and AD pathology. Patients with LRRK2 mutations frequently develop clinical dementia, and nearly half of patients with LRRK2-driven neurodegeneration develop tau or other pathology instead of synucleinopathy. LRRK2 is therefore a key regulator controlling protein aggregation and neurodegeneration, and defining the mechanisms by which LRRK2 mutations drive such varied prion-like pathology may lead to novel targeted therapeutics. The proposed study aims to characterize the proteostatic mechanisms upstream and downstream of LRRK2 using patient-derived neurons and rare postmortem LRRK2 patient brain tissue. The study has three goals. First, to define the role of LRRK2’s subcellular localization in its cellular functions and degradation, with a particular focus on LRRK2 microtubule association and endolysosomal activation. Second, to test the extent to which newly identified LRRK2 protein degradation pathways rescue neurotoxicity in patient-derived aged neurons and other disease relevant systems. Third, to define the mechanisms by which LRRK2 mutations can drive both synucleinopathy and tauopathy using real-time quaking-induced conversion (RT-QuIC), detailed neuropathology, and cell-type specific transcriptomics on a rare cohort of LRRK2 patient brain tissues. Overall, these studies should begin to define the mechanisms by which LRRK2 drives myriad neuropathology and provide insight into the relevance of LRRK2 as a therapeutic target for tauopathies.