Oligomerization of Lrrk controls actin severing and α-synuclein neurotoxicity in vivo

Background 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 alpha-synuclein within affected brain tissue. Methods We combine genetic analysis of Lrrk-associated toxicity in a penetrant Drosophila model of wild type human alpha-synuclein neurotoxicity with biochemical analyses and modeling of LRRK2 toxicity in human neurons and transgenic mouse models. Results We demonstrate that Lrrk and alpha-synuclein interact to promote neuronal degeneration through convergent effects on the actin cytoskeleton and downstream dysregulation of mitochondrial dynamics and function. We find specifically that monomers and dimers of Lrrk efficiently sever actin and promote normal actin dynamics in vivo. Oligomerization of Lrrk, which is promoted by dominant Parkinson's disease-causing mutations, reduces actin severing activity in vitro and promotes excess stabilization of F-actin in vivo. Importantly, a clinically protective Lrrk mutant reduces oligomerization and alpha-synuclein neurotoxicity. Conclusions Our findings provide a specific mechanistic link between two key molecules in the pathogenesis of Parkinson's disease, alpha-synuclein and LRRK2, and suggest potential new approaches for therapy development.

Automated summary

The interaction between Lrrk and alpha-synuclein promotes neuronal degeneration by affecting the actin cytoskeleton and mitochondrial dynamics. Oligomerization of Lrrk reduces actin severing activity and promotes excess stabilization of F-actin. A clinically protective Lrrk mutant reduces oligomerization and alpha-synuclein neurotoxicity, suggesting potential new approaches for therapy development in Parkinson's disease.