LRRK2 phosphorylates tubulin-associated tau but not the free molecule: LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth.
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.
Department of Biochemistry, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Japan. kawakami@kitasato-u.ac.jp
Fumitaka
F
Kawakami
Takatoshi
T
Yabata
Etsuro
E
Ohta
Tatsunori
T
Maekawa
Naoki
N
Shimada
Minori
M
Suzuki
Hiroko
H
Maruyama
Takafumi
T
Ichikawa
Fumiya
F
Obata
D000818:Animals; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008954:Models, Biological; D016501:Neurites / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034421:Sus scrofa; D014404:Tubulin / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D014404:Tubulin; D016875:tau Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases