USP10 deubiquitinates Tau, mediating its aggregation

Zhen Wei, Kuan Zeng, Jichang Hu, Xing Li, Fang Huang, Bin Zhang, Jian Zhi Wang, Rong Liu, Hong Lian Li, Xiaochuan Wang

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Normal Tau promotes the assembly and stabilization of microtubules, thus, maintaining axon transport. In Alzheimer’s disease (AD), Tau aggregation causes it to lose these above-mentioned functions. However, the molecular mechanism leading to Tau aggregation in AD remains ambiguous. Here, we report that USP10, one of the important deubiquitinases (DUBs), is involved in Tau aggregation. We found that USP10 is upregulated in postmortem human AD and APP/PS1 mice brains, but not in P301S mice brains. Moreover, in primary neuronal cultures, Aβ42 induces a dose-dependent USP10 upregulation, an increase in the levels of both total and phosphorylated Tau, as well as a markedly elevated Tau binding with USP10, that is accompanied by a significantly decreased Tau ubiquitination. In addition, overexpression of USP10 directly causes an increase in the levels of total and phosphorylated Tau, induces Tau aggregation, and delays in Tau degradation. Results from mass spectrometry, reciprocal immunoprecipitation, and immunofluorescence assays strongly prove Tau’s interaction with USP10. This is further supported by the Tau307–326K and Tau341–378K peptides’ competitive inhibition of Tau binding with USP10, attenuating Tau hyperphosphorylation and Tau deubiquitination. Together, our data strongly indicate that USP10 plays a critical role in mediating Tau aggregation via downregulating its ubiquitination and thus slowing down Tau turnover. Inhibition of USP10-Tau interaction might be therapeutically useful in the management of AD and related tauopathies.

Original languageEnglish
Article number726
JournalCell Death and Disease
Volume13
Issue number8
DOIs
StatePublished - Aug 2022
Externally publishedYes

Fingerprint

Dive into the research topics of 'USP10 deubiquitinates Tau, mediating its aggregation'. Together they form a unique fingerprint.

Cite this