LRRK2 phosphorylates tubulin-associated tau but not the free molecule: LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth.
LRRK2 phosphorylates tubulin-associated tau but not the free molecule: LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth.
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DOI：
10.1371/journal.pone.0030834
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Obata F
中科院分区：
文献类型：
--
作者：
Kawakami F;Yabata T;Ohta E;Maekawa T;Shimada N;Suzuki M;Maruyama H;Ichikawa T;Obata F
富含亮氨酸重复序列激酶2（LRRK 2）是一种含有多功能结构域的大蛋白激酶，已被鉴定为常染色体显性帕金森病（PD）的致病分子。在本研究中，我们首次证明了（i）LRRK 2以微管蛋白依赖性方式与tau相互作用;（ii）LRRK 2直接磷酸化微管蛋白相关的tau，但不磷酸化游离tau;（iii）LRRK 2磷酸化tau的Thr 181靶位点之一;（iv）PD相关的LRRK 2突变G2019 S和I2020 T，提高了tau磷酸化的程度。这些结果提供了tau是LRRK 2的生理底物的直接证据。此外，我们发现LRRK 2介导的tau蛋白磷酸化降低了其微管蛋白结合能力。我们的研究结果表明，LRRK 2作为磷酸化介导的tau蛋白从微管解离的生理调节剂发挥着重要作用，这是神经突生长和轴突运输所必需的微管动力学的一个组成部分。
Leucine-rich repeat kinase 2 (LRRK2), a large protein kinase containing multi-functional domains, has been identified as the causal molecule for autosomal-dominant Parkinson's disease (PD). In the present study, we demonstrated for the first time that (i) LRRK2 interacts with tau in a tubulin-dependent manner; (ii) LRRK2 directly phosphorylates tubulin-associated tau, but not free tau; (iii) LRRK2 phosphorylates tau at Thr181 as one of the target sites; and (iv) The PD-associated LRRK2 mutations, G2019S and I2020T, elevated the degree of tau-phosphorylation. These results provide direct proof that tau is a physiological substrate for LRRK2. Furthermore, we revealed that LRRK2-mediated phosphorylation of tau reduces its tubulin-binding ability. Our results suggest that LRRK2 plays an important role as a physiological regulator for phosphorylation-mediated dissociation of tau from microtubules, which is an integral aspect of microtubule dynamics essential for neurite outgrowth and axonal transport.
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影响因子：
6.1
作者：
Melrose HL;Dächsel JC;Behrouz B;Lincoln SJ;Yue M;Hinkle KM;Kent CB;Korvatska E;Taylor JP;Witten L;Liang YQ;Beevers JE;Boules M;Dugger BN;Serna VA;Gaukhman A;Yu X;Castanedes-Casey M;Braithwaite AT;Ogholikhan S;Yu N;Bass D;Tyndall G;Schellenberg GD;Dickson DW;Janus C;Farrer MJ
通讯作者：
Farrer MJ
影响因子：
7
作者：
Meixner, Andrea;Boldt, Karsten;Ueffing, Marius
通讯作者：
Ueffing, Marius
影响因子：
25
作者：
Li, Yanping;Liu, Wencheng;Oo, Tinmarla F.;Wang, Lei;Tang, Yi;Jackson-Lewis, Vernice;Zhou, Chun;Geghman, Kindiya;Bogdanov, Mikhail;Przedborski, Serge;Beal, M. Flint;Burke, Robert E.;Li, Chenjian
通讯作者：
Li, Chenjian
影响因子：
16.2
作者：
GOEDERT, M;SPILLANTINI, MG;CROWTHER, RA
通讯作者：
CROWTHER, RA
影响因子：
4.7
作者：
Gillardon, Frank
通讯作者：
Gillardon, Frank