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Updated: May 21, 2026
Efficient and Scalable Production of Full-length Human Huntingtin Variants in Mammalian Cells using a Transient Expression System
Published on: December 10, 2021
Impaired heat shock response in cells expressing full-length polyglutamine-expanded huntingtin
Sidhartha M Chafekar1, Martin L Duennwald
1Regenerative Biology Program, Boston Biomedical Research Institute, Watertown, Massachusetts, United States of America.
Insights
Huntington
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by polyglutamine (polyQ)-expanded huntingtin (Htt) protein.
- Cellular proteostasis, the maintenance of protein homeostasis, is implicated in HD pathogenesis.
- Understanding the precise molecular mechanisms of neurodegeneration in HD is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the role of cellular proteostasis, specifically the heat shock response, in HD.
- To explore how polyglutamine-expanded huntingtin affects the heat shock response under stress conditions.
- To identify potential molecular targets for therapeutic intervention in Huntington's disease.
Main Methods:
- Analysis of proteostatic capacity in cells expressing full-length polyQ-expanded huntingtin under varying stress conditions.
- Measurement of heat shock transcription factor 1 (HSF1) and heat shock protein 70 (HSP70) levels in cellular and mouse models of HD.
- Assessment of the heat shock response's effectiveness in the presence of polyQ-expanded huntingtin.
Main Results:
- Cells expressing polyQ-expanded huntingtin show adequate proteostasis under normal conditions but impaired heat shock response under stress.
- Reduced levels of heat shock transcription factor 1 (HSF1) were observed in cells with polyQ-expanded huntingtin.
- Lower levels of HSF1 and HSP70 were found in the striata of Huntington's disease knock-in mice compared to wild-type mice.
Conclusions:
- Full-length, non-aggregated polyQ-expanded huntingtin impairs the heat shock response induction under cellular stress.
- This impairment leads to reduced cellular resilience and increased susceptibility to damage in Huntington's disease.
- Targeting the heat shock response pathway may offer a novel therapeutic strategy for Huntington's disease.
Abstract:
The molecular mechanisms by which polyglutamine (polyQ)-expanded huntingtin (Htt) causes neurodegeneration in Huntington's disease (HD) remain unclear. The malfunction of cellular proteostasis has been suggested as central in HD pathogenesis and also as a target of therapeutic interventions for the treatment of HD. We present results that offer a previously unexplored perspective regarding impaired proteostasis in HD. We find that, under non-stress conditions, the proteostatic capacity of cells expressing full length polyQ-expanded Htt is adequate. Yet, under stress conditions, the presence of polyQ-expanded Htt impairs the heat shock response, a key component of cellular proteostasis. This impaired heat shock response results in a reduced capacity to withstand the damage caused by cellular stress. We demonstrate that in cells expressing polyQ-expanded Htt the levels of heat shock transcription factor 1 (HSF1) are reduced, and, as a consequence, these cells have an impaired a heat shock response. Also, we found reduced HSF1 and HSP70 levels in the striata of HD knock-in mice when compared to wild-type mice. Our results suggests that full length, non-aggregated polyQ-expanded Htt blocks the effective induction of the heat shock response under stress conditions and may thus trigger the accumulation of cellular damage during the course of HD pathogenesis.
