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Updated: Aug 6, 2025
07:08
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
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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
Summary
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.
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