PTK2 regulates tau-induced neurotoxicity via phosphorylation of p62 at Ser403

Abstract

Tau is a microtubule-associated protein that forms insoluble filaments that accumulate as neurofibrillary tangles in neurodegenerative diseases such as Alzheimer’s disease and other related tauopathies. A relationship between abnormal Tau accumulation and ubiquitin–proteasome system impairment has been reported. However, the molecular mechanism linking Tau accumulation and ubiquitin proteasome system (UPS) dysfunction remains unclear. Here, we show that overexpression of wild-type or mutant (P301L) Tau increases the abundance of polyubiquitinated proteins and activates the autophagy–lysosome pathway in mammalian neuronal cells. Previous studies found that PTK2 inhibition mitigates toxicity induced by UPS impairment. Thus, we investigated whether PTK2 inhibition can attenuate Tau-induced UPS impairment and cell toxicity. We found that PTK2 inhibition significantly reduces Tau-induced death in mammalian neuronal cells. Moreover, overexpression of WT or mutant Tau increased the phosphorylation levels of PTK2 and p62. We also confirmed that PTK2 inhibition suppresses Tau-induced phosphorylation of PTK2 and p62. Furthermore, PTK2 inhibition significantly attenuated the climbing defect and shortened the lifespan in the Drosophila model of tauopathy. In addition, we observed that phosphorylation of p62 is markedly increased in Alzheimer’s disease patients with tauopathies. Taken together, our results indicate that the UPS dysfunction induced by Tau accumulation might contribute directly to neurodegeneration in tauopathies and that PTK2 could be a promising therapeutic target for tauopathies.

Keywords:

• MAPT/Tau
• PTK2
• p62
• Alzheimer’s disease
• ubiquitin-proteasome system

Ethics approval

Human tissue experiments were performed in accordance with the guidelines of the Institutional Review Bord (IRB) at the Korea Brain Research Institute. Postmortem tissue samples were obtained from the Netherlands brain bank (NBB), Netherlands Institute for Neuroscience, Amsterdam. This study was approved by the IRB at Korea Brain Research Institute (#201610-BR-004–01).

Author contributions

S.L., M.J., and Y.K., and planned and performed the experiments. Y.-M.J., S.K., and K.J.L. provided ideas for the project and participated in writing the paper. S.L., M.J., and H.-J.K. wrote the paper. All authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research was supported by the KBRI basic research program through Korea Brain Research Institute funded by Ministry of Science and ICT [22-BR-03–02]; the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future Planning [NRF-2020R1A2C4002366, NRF-2021R1C1C1008688]; and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, South Korea [grant number: HI14C1135].