LRRK2 phosphorylates tubulin-associated tau but not the free molecule: LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth

• Published in: PloS one Vol. 7; no. 1; p. e30834
• Main Authors: Kawakami, Fumitaka, Yabata, Takatoshi, Ohta, Etsuro, Maekawa, Tatsunori, Shimada, Naoki, Suzuki, Minori, Maruyama, Hiroko, Ichikawa, Takafumi, Obata, Fumiya
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.01.2012; Public Library of Science (PLoS)
• Subjects: Amino acids; Animals; Axonal transport; Axonogenesis; B cells; Biology; Brain; Cell Line, Tumor; Dissociation; Drosophila; Gene Knockdown Techniques; Humans; Kinases; Leucine; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; LRRK2 protein; Medical research; Medicine; Microtubules; Models, Biological; Movement disorders; Mutation; Neurites - metabolism; Neurodegenerative diseases; Parkinson's disease; Phosphorylation; Physiological aspects; Physiology; Protein Binding; Protein kinase; Protein kinase C; Protein kinases; Protein-Serine-Threonine Kinases - metabolism; Rodents; Sus scrofa; tau Proteins - metabolism; Tubulin; Tubulin - metabolism; United States > US; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0030834

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.