Lrrk promotes tau neurotoxicity through dysregulation of actin and mitochondrial dynamics

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson disease.Genetics and neuropathology link Parkinson disease with the microtubule-binding protein tau, but the mechanism of action of LRRK2 mutations and the molecular connection between tau and Parkinson disease are unclear.Here, we investigate the interaction of LRRK and tau in Drosophila and mouse models of tauopathy.We find that either increasing or decreasing the level of fly Lrrk enhances tau neurotoxicity, which is further exacerbated by expressing Lrrk with dominantly acting Parkinson disease-associated mutations.At the cellular level, altering Lrrk expression promotes tau neurotoxicity via excess stabilization of filamentous actin (F-actin) and subsequent mislocalization of the critical mitochondrial fission protein dynamin-1-like protein (Drp1).Biochemically, monomeric LRRK2 exhibits actin-severing activity, which is reduced as increasing concentrations of wild-type LRRK2, or expression of mutant forms of LRRK2 promote oligomerization of the protein.Overall, our findings provide a potential mechanistic basis for a dominant negative mechanism in LRRK2-mediated Parkinson disease, suggest a common molecular pathway with other familial forms of Parkinson disease linked to abnormalities of mitochondrial dynamics and quality control, and raise the possibility of new therapeutic approaches to Parkinson disease and related disorders. Author summaryParkinson disease is a common and debilitating neurodegenerative disorder.Family and larger population-based studies have revealed a number of genes important in the development and progression of the disease, but specific mechanisms linking these seemingly unrelated genes and proteins with specific cellular pathways within affected neurons have often remained elusive.Here, we connect the pathobiology of two proteins associated with Parkinson disease through genetics and neuropathology in patients, leucine-rich repeat kinase 2 (LRRK2) and tau.