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Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
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Global changes to the ubiquitin system in Huntington's disease
Eric J Bennett1, Thomas A Shaler, Ben Woodman
1Department of Biological Sciences, Stanford University, Stanford, California 94305, USA.
Nature
|August 10, 2007
Summary
Huntington's disease (HD) involves brain accumulation of polyubiquitin chains, indicating impaired ubiquitin-proteasome system (UPS) function. This dysfunction is an early and consistent feature of HD pathology in both mouse models and human patients.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by CAG repeat expansion in the huntingtin (HTT) gene.
- Ubiquitin accumulation in inclusion bodies suggests a role for ubiquitin metabolism dysfunction in HD pathogenesis.
- The ubiquitin-proteasome system (UPS) regulates critical cellular processes, but its role in HD remains debated.
Purpose of the Study:
- To investigate the function of the UPS in Huntington's disease pathogenesis.
- To determine if UPS dysfunction is a consistent feature of HD pathology.
- To identify potential biomarkers of UPS dysfunction in HD.
Main Methods:
- Utilized a mass-spectrometry-based method to quantify polyubiquitin chains.
- Analyzed brain tissue from R6/2 transgenic mice, knock-in HD mouse models, and human HD patients.
- Measured the abundance of different types of polyubiquitin chains (Lys 48, Lys 63, Lys 11-linked).
Main Results:
- Accumulation of Lys 48-linked polyubiquitin chains was observed early in HD pathogenesis in all models studied.
- This accumulation serves as a reliable endogenous biomarker of UPS dysfunction in HD.
- Lys 63- and Lys 11-linked polyubiquitin chains also accumulated in the R6/2 mouse model.
Conclusions:
- UPS dysfunction is a consistent and early feature of Huntington's disease pathology.
- Global changes in the ubiquitin system are more extensive in HD than previously recognized.
- These findings highlight the UPS as a potential therapeutic target for HD.
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