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Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
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Multiple discrete soluble aggregates influence polyglutamine toxicity in a Huntington's disease model system
Wen Xi1, Xin Wang1, Thomas M Laue1
1Department of Molecular, Cellular, and Biomedical Sciences, Rudman Hall, University of New Hampshire, NH 03824, Durham, USA.
Scientific Reports
|October 11, 2016
Summary
Huntington's disease (HD) research shows that toxic huntingtin protein (Htt) aggregates form early and change over time. Targeting these dynamic soluble aggregates may be key to treating neurodegenerative diseases.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by expanded polyglutamine (polyQ) stretches in the huntingtin protein (Htt).
- The size and diversity of soluble Htt-polyQ aggregates, which are linked to cytotoxicity, remain poorly understood.
- Current models do not fully account for the formation of soluble aggregates by non-toxic Htt variants.
Purpose of the Study:
- To investigate the characteristics and dynamics of soluble Htt-polyQ aggregates in a yeast model of HD.
- To determine the relationship between Htt-polyQ aggregate size, formation over time, and cytotoxicity.
- To explore how factors influencing HD pathogenesis affect Htt-polyQ aggregation.
Main Methods:
- Utilized analytical ultracentrifugation to analyze soluble Htt-polyQ aggregates.
- Employed a yeast HD model system with varying polyQ lengths (Htt-25Q and Htt-103Q).
- Monitored aggregate formation and size at different time points (6 hr and 24 hr) post-induction.
Main Results:
- Both non-toxic Htt-25Q and cytotoxic Htt-103Q formed soluble aggregates (29S to 200S) early in the process.
- Htt-103Q aggregation dynamics changed over time, with mid-sized and large aggregates present at 6 hr, and primarily mid-sized aggregates at 24 hr.
- Factors reducing Htt-103Q cytotoxicity altered its aggregation pattern, with mid-sized aggregates at 6 hr showing the strongest correlation with cytotoxicity.
Conclusions:
- Soluble Htt-polyQ aggregates form earlier and are more diverse than previously thought, necessitating a reevaluation of existing models.
- The dynamic changes in Htt-polyQ aggregate profiles over time are crucial for understanding HD pathogenesis.
- Therapeutic strategies for HD and other neurodegenerative diseases should consider targeting the dynamic nature of soluble protein aggregation.
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