LRRK2 phosphorylates tubulin-associated tau but not the free molecule: LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth |
| |
Authors: | Kawakami Fumitaka Yabata Takatoshi Ohta Etsuro Maekawa Tatsunori Shimada Naoki Suzuki Minori Maruyama Hiroko Ichikawa Takafumi Obata Fumiya |
| |
Institution: | Department of Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan. kawakami@kitasato-u.ac.jp |
| |
Abstract: | 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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|