Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington\u2019s disease

Rocio Gomez-Pastor,Alex M Jaeger,Sergey S Akimov,Donald C Lo,Alejandro Aballay,Christopher A Ross,Elisa Cabiscol,Spencer U Mckinstry,Argenia Doss,Eileen T Burchfiel,Dennis J Thiele,Daniel W Neef,Cagla Eroglu

doi:10.1038/ncomms14405

Abstract

Huntington’s Disease (HD) is a neurodegenerative disease caused by poly-glutamine expansion in the Htt protein, resulting in Htt misfolding and cell death. Expression of the cellular protein folding and pro-survival machinery by heat shock transcription factor 1 (HSF1) ameliorates biochemical and neurobiological defects caused by protein misfolding. We report that HSF1 is degraded in cells and mice expressing mutant Htt, in medium spiny neurons derived from human HD iPSCs and in brain samples from patients with HD. Mutant Htt increases CK2α′ kinase and Fbxw7 E3 ligase levels, phosphorylating HSF1 and promoting its proteasomal degradation. An HD mouse model heterozygous for CK2α′ shows increased HSF1 and chaperone levels, maintenance of striatal excitatory synapses, clearance of Htt aggregates and preserves body mass compared with HD mice homozygous for CK2α′. These results reveal a pathway that could be modulated to prevent neuronal dysfunction and muscle wasting caused by protein misfolding in HD.

Highlights

Huntington’s Disease (HD) is a neurodegenerative disease caused by poly-glutamine expansion in the Htt protein, resulting in Htt misfolding and cell death
We performed these studies under control (37 °C) and heat shock conditions (42 °C), allowing us to both analyse the defect in heat shock transcription factor 1 (HSF1) under polyQ protein expressing conditions and explore the expression of inducible HSF1 target genes (Fig. 1a)
HSF1 plays a critical role in activating genes encoding proteins that function in protein quality control, mitochondrial function and cellular pro-survival factors that ameliorate defects in neuronal function and survival in HD

Summary

Introduction

Huntington’s Disease (HD) is a neurodegenerative disease caused by poly-glutamine expansion in the Htt protein, resulting in Htt misfolding and cell death. An HD mouse model heterozygous for CK2a0 shows increased HSF1 and chaperone levels, maintenance of striatal excitatory synapses, clearance of Htt aggregates and preserves body mass compared with HD mice homozygous for CK2a0. These results reveal a pathway that could be modulated to prevent neuronal dysfunction and muscle wasting caused by protein misfolding in HD. Increased expression of chaperones such as Hsp[104], Hsp[70], Hsp[40] and Hsp[27], or critical components in the autophagy pathway, ameliorates protein aggregation and cell death in cellular, fly, worm and mouse polyQ expansion disease models[8,9,10,11]. A heterozygous HSF1 mouse model of spinal and bulbar muscular atrophy with a pathogenic polyQ repeat in the androgen receptor (AR), exhibited increased AR-polyQ aggregates in neurons and non-neuronal tissues and enhanced neurodegeneration[25,26]

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Results

Conclusion