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USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L-SMAD pathway

Tao Zhang1,2, Goran Periz1,2, Yu-Ning Lu1,2

  • 1Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205.

Proceedings of the National Academy of Sciences of the United States of America
|October 27, 2020
PubMed

Insights

Researchers identified USP7 as a key regulator in cellular protein quality control, defending against neurodegenerative disease triggers like protein misfolding. This discovery offers new therapeutic targets for diseases such as amyotrophic lateral sclerosis (ALS).

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Genetics

Background:

  • Protein misfolding and aggregation disrupt cellular homeostasis, contributing to neurodegenerative diseases like amyotrophic lateral sclerosis (ALS).
  • Effective protein quality control mechanisms are crucial for neuronal health and preventing proteotoxicity.

Purpose of the Study:

  • To identify novel regulators of protein quality control involved in neuroprotection.
  • To investigate the role of USP7 in defending against proteotoxicity in neurodegenerative disease models.

Main Methods:

  • Genome-wide screen in a *Caenorhabditis elegans* model of SOD1-linked ALS.
  • Functional studies of USP7 orthologs in *Drosophila* and mammalian cells.
  • Investigation of USP7's interaction with the SMAD2/transforming growth factor β pathway and NEDD4L.

Main Results:

  • USP7 was identified as a suppressor of proteotoxicity in the nervous system across multiple species.
  • USP7 enhances the clearance of misfolded proteins by modulating SMAD2 activity and activating autophagy.
  • USP7 deubiquitinates NEDD4L, preventing SMAD2 degradation; its inhibition exacerbates proteotoxicity in neurons.
  • Dysregulation of SMAD2 was observed in the nervous systems of ALS patients.

Conclusions:

  • USP7 acts as a critical regulatory switch in the protein quality control system, protecting against proteotoxicity.
  • The identified USP7-SMAD2 pathway represents a novel therapeutic target for proteotoxicity-associated neurodegenerative diseases, including ALS.
Keywords:
NEDD4LSMADUSP7protein misfoldingprotein quality control

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