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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
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USP10 deubiquitinates Tau, mediating its aggregation.

Zhen Wei1, Kuan Zeng1, Jichang Hu1

  • 1Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Cell Death & Disease
|August 20, 2022
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Summary

The deubiquitinase USP10 promotes Tau aggregation in Alzheimer's disease (AD) by reducing Tau ubiquitination and slowing its degradation. Inhibiting USP10-Tau interaction may offer a therapeutic strategy for AD and tauopathies.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Normal Tau stabilizes microtubules and maintains axon transport.
  • In Alzheimer's disease (AD), Tau aggregation disrupts these functions, but the underlying mechanisms are unclear.
  • Deubiquitinases (DUBs) play crucial roles in protein regulation, including Tau.

Purpose of the Study:

  • To investigate the role of USP10, a deubiquitinase, in Tau aggregation in Alzheimer's disease.
  • To elucidate the molecular mechanisms by which USP10 influences Tau pathology.

Main Methods:

  • Western blotting and immunohistochemistry to assess USP10 and Tau levels in human AD brains and mouse models.
  • Primary neuronal cultures treated with Aβ42 to study USP10-mediated Tau changes.
  • Mass spectrometry, co-immunoprecipitation, and immunofluorescence assays to confirm USP10-Tau interaction.
  • Peptide competition assays to validate the interaction site and its functional consequences.

Main Results:

  • USP10 is upregulated in human AD and APP/PS1 mouse brains.
  • Aβ42 induces USP10 upregulation, increased total and phosphorylated Tau, and decreased Tau ubiquitination.
  • USP10 overexpression leads to Tau aggregation, hyperphosphorylation, and reduced degradation.
  • Direct interaction between USP10 and Tau was confirmed, with specific peptides inhibiting this interaction.

Conclusions:

  • USP10 plays a critical role in mediating Tau aggregation in AD by reducing Tau ubiquitination and slowing Tau turnover.
  • Targeting the USP10-Tau interaction presents a potential therapeutic avenue for managing AD and related tauopathies.