Oligomerization of Lrrk controls actin severing and α-synuclein neurotoxicity in vivo.
Oligomerization of Lrrk controls actin severing and α-synuclein neurotoxicity in vivo.
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DOI：
10.1186/s13024-021-00454-3
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发表时间：
2021-05-24
影响因子：
15.1
通讯作者：
Feany MB
中科院分区：
文献类型：
--
作者：
Sarkar S;Bardai F;Olsen AL;Lohr KM;Zhang YY;Feany MB
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. 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. 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 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. Our 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. The online version contains supplementary material available at 10.1186/s13024-021-00454-3.
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影响因子：
16.2
作者：
Giaime E;Tong Y;Wagner LK;Yuan Y;Huang G;Shen J
通讯作者：
Shen J
影响因子：
3.3
作者：
Caesar, M.;Felk, S.;Gillardon, F.
通讯作者：
Gillardon, F.
DOI：
10.1073/pnas.1318306111
发表时间：
2014-02-18
影响因子：
11.1
作者：
Beilina, Alexandria;Rudenko, Iakov N.;Cookson, Mark R.
通讯作者：
Cookson, Mark R.
影响因子：
168.9
作者：
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通讯作者：
Destée, A
影响因子：
5.3
作者：
Bardai, Farah H.;Wang, Liqun;Feany, Mel B.
通讯作者：
Feany, Mel B.