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. ; We thank Drs D. Rubinsztein and D. Merry for cell lines, Glyn Noguchi, Rhona Ke and Caley Burrus for technical assistance, Dr Isidre Ferrer for providing the Barcelona Biobank human samples and Dr M. Alba Sorolla for preparation of samples. We thank Dr Seldin for providing CK2a0 (þ/ ) mice and Dr R. Morimoto for providing C. elegans strains. We thank Dr T. Slotkin for help with statistical analysis. This work was supported by National Institutes of Health grant R01 NS065890 to D.J.T., R01 DA031833 and R01 NS096352 to C.E., R01GM070977 to A.A., U24NS069422/U24NS078378 and R21NS083365 to C.A.R., a Holland Trice Scholar Award to C.E. and D.J.T., NIH Predoctoral Fellowship F31GM119375 to E.T.B. and a Postdoctoral Fellowship from the Huntington’s Disease Society of America to R.G.P.