The heat shock response, determined by QuantiGene multiplex, is impaired in HD mouse models and not caused by HSF1 reduction

Casandra Gomez-Paredes,Bridget A Taxy,Michael A Mason,Paolo Paganetti,Gillian P Bates,Aikaterini S Papadopoulou

doi:10.1038/s41598-021-88715-5

Abstract

Huntington’s disease (HD) is a devastating neurodegenerative disorder, caused by a CAG/polyglutamine repeat expansion, that results in the aggregation of the huntingtin protein, culminating in the deposition of inclusion bodies in HD patient brains. We have previously shown that the heat shock response becomes impaired with disease progression in mouse models of HD. The disruption of this inducible arm of the proteostasis network is likely to exacerbate the pathogenesis of this protein-folding disease. To allow a rapid and more comprehensive analysis of the heat shock response, we have developed, and validated, a 16-plex QuantiGene assay that allows the expression of Hsf1 and nine heat shock genes, to be measured directly, and simultaneously, from mouse tissue. We used this QuantiGene assay to show that, following pharmacological activation in vivo, the heat shock response impairment in tibialis anterior, brain hemispheres and striatum was comparable between zQ175 and R6/2 mice. In contrast, although a heat shock impairment could be detected in R6/2 cortex, this was not apparent in the cortex from zQ175 mice. Whilst the mechanism underlying this impairment remains unknown, our data indicated that it is not caused by a reduction in HSF1 levels, as had been reported.

Highlights

Huntington’s disease (HD) is a devastating neurodegenerative disorder, caused by a CAG/ polyglutamine repeat expansion, that results in the aggregation of the huntingtin protein, culminating in the deposition of inclusion bodies in HD patient brains
In order to investigate whether the basal or activated levels of heat shock factor 1 (HSF1) were altered in zQ175 mice with disease progression, we first conducted a comprehensive analysis of HSF1 antibodies
That the heat shock response becomes impaired with disease progression in HD utilised the R6/2 transgenic and HdhQ150 knockin mouse models

Summary

Introduction

Huntington’s disease (HD) is a devastating neurodegenerative disorder, caused by a CAG/ polyglutamine repeat expansion, that results in the aggregation of the huntingtin protein, culminating in the deposition of inclusion bodies in HD patient brains. Huntington’s disease (HD) is a progressive neurodegenerative disorder, of autosomal dominant inheritance, caused by the expansion of a CAG repeat, within exon 1 of the huntingtin (HTT) gene[1,2] This encodes an abnormally long polyglutamine tract that leads to the formation of insoluble aggregates in brains and other tissues from HD patients as well as in mouse models of the disease[3,4,5,6,7,8]. We previously reported that HSF1 activation and heat shock gene induction, by the pulsed treatment with the HSP90 inhibitor NVP-HSP99025, ameliorated some motor phenotypes and reduced the aggregate load in brain and muscle of R6/2 mice These effects were transient, because the ability to mount a heat shock response became impaired with disease p rogression[26]. It was not related to the levels or activation of HSF1, but there was a decreased HSF1 occupancy at heat shock gene promoters which correlated with the hypoacetylation of histone H 426

Methods

Results

Conclusion