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.
Highlights
Tau is a microtubule-associated protein found predominantly in the central nervous system and expressed mainly in neuronal axons [1]
We demonstrate that Leucine-rich repeat kinase 2 (LRRK2) directly phosphorylates tau in the presence of tubulin and facilitates dissociation of tau from tubulin, indicating that LRRK2 is of considerable physiological importance in microtubules dynamics
We found that both tau and tubulin were co-precipitated with LRRK2 (Fig. 1A)
Summary
Tau is a microtubule-associated protein found predominantly in the central nervous system and expressed mainly in neuronal axons [1]. Tau has six splicing isoforms, ranging in size from 352 to 441 amino acid residues [2]. The shortest tau isoform is expressed only in fetal brain, and the other five are expressed developmentally in the adult brain [3]. Tau drives neurite outgrowth by promoting the assembly of microtubules, which is critical for the establishment of neuronal cell polarity [4]. In Alzheimer’s disease and other neurodegenerative diseases, such as frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), tau becomes highly phosphorylated and forms a paired helical filament [3]. Hyperphosphorylated tau-based neurofibrillary lesions are the predominant brain pathology in these disorders, which are referred to collectively as ‘‘tauopathies’’ [5]
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