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

Molecular Neurodegeneration

Ying-Yi Zhang¹  Abby L. Olsen²  Souvarish Sarkar³  Kelly M. Lohr³  Farah Bardai³  Mel B. Feany³ 

[1] Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA;Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA;Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA;

关键词: Parkinson’s disease;    LRRK2;    α-synuclein;    F-actin;    Drp1;    Mitochondria;    Drosophila;    Genetics;    Dopamine neuron;    Bioenergetics;   

DOI  :  10.1186/s13024-021-00454-3

来源: Springer

【 摘 要 】

BackgroundMutations 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.MethodsWe 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.ResultsWe 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 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 α-synuclein neurotoxicity.ConclusionsOur findings provide a specific mechanistic link between two key molecules in the pathogenesis of Parkinson’s disease, α-synuclein and LRRK2, and suggest potential new approaches for therapy development.

【 授权许可】

CC BY