Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations.
Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations.
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DOI：
10.1038/ncomms6245
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发表时间：
2014-10-15
影响因子：
16.6
通讯作者：
De Vos, Kurt J.
中科院分区：
文献类型：
--
作者：
Godena, Vinay K.;Brookes-Hocking, Nicholas;Moller, Annekathrin;Shaw, Gary;Oswald, Matthew;Sancho, Rosa M.;Miller, Christopher C. J.;Whitworth, Alexander J.;De Vos, Kurt J.
富含亮氨酸的重复激酶2（LRRK 2）突变是帕金森病最常见的遗传原因。LRRK 2是影响许多细胞过程的多功能蛋白质，并且已被描述为结合微管。假设基于微管的轴突运输缺陷导致帕金森病，但LRRK 2突变是否影响这一过程以介导发病机制尚不清楚。在这里，我们发现，LRRK 2含有致病性Roc-COR结构域突变（R1441 C，Y1699 C）优先与脱乙酰微管，并抑制轴突运输在初级神经元和果蝇，造成运动缺陷在体内。在体外，使用去乙酰化酶抑制剂或微管蛋白乙酰化酶α TAT 1增加微管乙酰化可以防止突变型LRRK 2与微管的结合，而去乙酰化酶抑制剂阿司他丁A（TSA）可以恢复轴突运输。体内敲低脱乙酰酶HDAC 6和Sirt 2或施用TSA拯救轴突运输和运动行为。因此，这项研究揭示了帕金森病的致病机制和潜在的干预措施。 激酶LRRK 2的突变与帕金森病有关。Godena等人发现，疾病相关的LRRK 2突变促进其与脱乙酰化微管的结合，并导致轴突运输和果蝇运动行为的缺陷，这些缺陷可以通过增强微管蛋白乙酰化来逆转。
Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson’s disease. LRRK2 is a multifunctional protein affecting many cellular processes and has been described to bind microtubules. Defective microtubule-based axonal transport is hypothesized to contribute to Parkinson’s disease, but whether LRRK2 mutations affect this process to mediate pathogenesis is not known. Here we find that LRRK2 containing pathogenic Roc-COR domain mutations (R1441C, Y1699C) preferentially associates with deacetylated microtubules, and inhibits axonal transport in primary neurons and in Drosophila, causing locomotor deficits in vivo. In vitro, increasing microtubule acetylation using deacetylase inhibitors or the tubulin acetylase αTAT1 prevents association of mutant LRRK2 with microtubules, and the deacetylase inhibitor trichostatin A (TSA) restores axonal transport. In vivo knockdown of the deacetylases HDAC6 and Sirt2, or administration of TSA rescues both axonal transport and locomotor behavior. Thus, this study reveals a pathogenic mechanism and a potential intervention for Parkinson’s disease. Mutations in the kinase LRRK2 are associated with Parkinson’s disease. Godena et al. find that disease-associated LRRK2 mutations promote its binding to deacetylated microtubules, and cause defects in axonal transport and Drosophila locomotor behaviour that can be reversed by enhancing tubulin acetylation.
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影响因子：
9.2
作者：
De Vos, KJ;Allan, VJ;Sheetz, MP
通讯作者：
Sheetz, MP
影响因子：
64.8
作者：
Hubbert, C;Guardiola, A;Yao, TP
通讯作者：
Yao, TP
DOI：
10.1083/jcb.200303138
发表时间：
2003-05-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ackerley S;Thornhill P;Grierson AJ;Brownlees J;Anderton BH;Leigh PN;Shaw CE;Miller CC
通讯作者：
Miller CC
影响因子：
4.7
作者：
Gillardon, Frank
通讯作者：
Gillardon, Frank
影响因子：
3.7
作者：
Guo, Luxuan;Gandhi, Payal N.;Chen, Shu G.
通讯作者：
Chen, Shu G.