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

ABSTRACT:

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 α-synuclein within affected brain tissue.

Methods

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.

Results

We demonstrate that Lrrk and α-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 dyn

SUBMITTER: Sarkar S 

PROVIDER: S-EPMC8142648 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature