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Ubiquitin-modifying enzymes in Huntington's disease

Karen A Sap1, Karlijne W Geijtenbeek1, Sabine Schipper-Krom1

  • 1Department of Medical Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Frontiers in Molecular Biosciences
|March 17, 2023
PubMed

Insights

Huntington's disease (HD) involves mutant huntingtin (mHTT) protein aggregation. Targeting mHTT for degradation via the ubiquitin-proteasome system (UPS) offers a therapeutic strategy to clear toxic proteins and slow disease progression.

Area of Science:

  • Neurodegenerative disease research
  • Molecular biology
  • Genetics

Background:

  • Huntington's disease (HD) is caused by a CAG repeat expansion in the HTT gene, leading to mutant huntingtin (mHTT) protein with a polyglutamine expansion.
  • mHTT aggregation and neurotoxicity are key pathological features of HD.
  • The ubiquitin-proteasome system (UPS) is crucial for protein degradation and may offer a pathway to clear mHTT.

Purpose of the Study:

  • To investigate the role of the UPS in clearing mHTT.
  • To identify ubiquitin-modifying enzymes that can enhance mHTT degradation.
  • To explore therapeutic strategies for Huntington's disease by targeting mHTT clearance.

Main Methods:

  • Analysis of mHTT ubiquitination compared to wild-type HTT (wtHTT).
  • Identification and characterization of ubiquitin-modifying enzymes associated with mHTT.
  • Investigating the interaction between mHTT and the proteostasis machinery.

Main Results:

  • mHTT exhibits different ubiquitination patterns compared to wtHTT.
  • Specific ubiquitin-modifying enzymes are linked to mHTT turnover.
  • The UPS can degrade mHTT when properly targeted.

Conclusions:

  • The UPS is a viable pathway for clearing mHTT in Huntington's disease.
  • Modulating ubiquitin-modifying enzymes could enhance mHTT degradation.
  • Targeting proteostasis offers a potential therapeutic approach for HD.

Keywords:
Huntington’s diseasedeubiquitinating enzymehuntingtinligaseneurodegenerative diseaseproteasomeproteostasisubiquitin

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