Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington’s disease

Rocio Gomez-Pastor, Eileen T. Burchfiel, Daniel W. Neef, Alex M. Jaeger, Elisa Cabiscol, Spencer U. McKinstry, Argenia Doss, Alejandro Aballay, Donald C. Lo, Sergey S. Akimov, Christopher A. Ross, Cagla Eroglu and Dennis J. Thiele ()
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Rocio Gomez-Pastor: Duke University School of Medicine
Eileen T. Burchfiel: Duke University School of Medicine
Daniel W. Neef: Duke University School of Medicine
Alex M. Jaeger: Duke University School of Medicine
Elisa Cabiscol: Departament de Ciencies Mediques Basiques, IRB Lleida, Universitat de Lleida
Spencer U. McKinstry: Duke University School of Medicine
Argenia Doss: Duke University School of Medicine
Alejandro Aballay: Duke University School of Medicine
Donald C. Lo: Duke University School of Medicine
Sergey S. Akimov: Johns Hopkins University School of Medicine
Christopher A. Ross: Johns Hopkins University School of Medicine
Cagla Eroglu: Duke University School of Medicine
Dennis J. Thiele: Duke University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14405

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