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Investigating the mechanisms of the heat shock response impairment in Huntington’s disease mouse models

Gomez Paredes, C; (2022) Investigating the mechanisms of the heat shock response impairment in Huntington’s disease mouse models. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Huntington’s disease (HD) is a neurodegenerative disease caused by the expansion of a CAG repeat within exon 1 of the huntingtin (HTT) gene. This produces a mutant HTT protein with an abnormally long polyglutamine stretch, which is prone to misfold and form aggregates, as detected in HD patients and mouse models, and which have aberrant interactions with members of key cellular pathways that become disrupted. The heat shock response is a cytoprotective mechanism that aims to prevent and reduce aggregation and maintain proteome integrity. It is regulated by heat shock factor 1 (HSF1) which, under stress conditions, activates the transcription of the heat shock genes. In this thesis, a comprehensive analysis of the heat shock response has been described for HD mouse models R6/2 and zQ175, after in vivo pharmacological induction with the compound NVP-HSP990. The expression of Hsf1 and nine heat shock genes was measured from mouse tissue lysates by a QuantiGene multiplex assay, developed and validated for this purpose. Evidence of an impairment of the heat shock response was found in brain hemispheres, tibialis anterior and striatum of both models, with less consistent evidence in the cortex. As a potential cause of this dysregulation, HSF1 levels were analysed in brain and muscle, however, a decrease in HSF1 was not detected in either tissue. SIRT1 can deacetylate HSF1 and maintain it in a competent state, bound to heat shock gene promoters. SIRT1 levels decline with disease progression in HD mouse models, therefore, whether a decreased SIRT1 activity could be responsible for the impaired heat shock response was investigated. The analysis of the heat shock gene expression with QuantiGene revealed that Sirt1 overexpression on R6/2 mice did not significantly improve the heat shock response impairment in brain or tibialis anterior.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Investigating the mechanisms of the heat shock response impairment in Huntington’s disease mouse models
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10141870
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