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, Dennis J. Thiele

Research output: Contribution to journalArticle

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.

LanguageEnglish (US)
Article number14405
JournalNature Communications
Volume8
DOIs
StatePublished - Feb 13 2017

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Transcription factors
Huntington Disease
Transcription Factors
shock
degradation
Degradation
heat
proteins
mice
Neurodegenerative diseases
Protein folding
Corpus Striatum
Proteins
Ubiquitin-Protein Ligases
glutamine
Protein Folding
synapses
Cell death
Neurodegenerative Diseases
machinery

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Gomez-Pastor, R., Burchfiel, E. T., Neef, D. W., Jaeger, A. M., Cabiscol, E., McKinstry, S. U., ... Thiele, D. J. (2017). Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington's disease. Nature Communications, 8, [14405]. DOI: 10.1038/ncomms14405

Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington's disease. / Gomez-Pastor, Rocio; Burchfiel, Eileen T.; Neef, Daniel W.; Jaeger, Alex M.; Cabiscol, Elisa; McKinstry, Spencer U.; Doss, Argenia; Aballay, Alejandro; Lo, Donald C.; Akimov, Sergey S.; Ross, Christopher A.; Eroglu, Cagla; Thiele, Dennis J.

In: Nature Communications, Vol. 8, 14405, 13.02.2017.

Research output: Contribution to journalArticle

Gomez-Pastor, R, Burchfiel, ET, Neef, DW, Jaeger, AM, Cabiscol, E, McKinstry, SU, Doss, A, Aballay, A, Lo, DC, Akimov, SS, Ross, CA, Eroglu, C & Thiele, DJ 2017, 'Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington's disease' Nature Communications, vol 8, 14405. DOI: 10.1038/ncomms14405
Gomez-Pastor R, Burchfiel ET, Neef DW, Jaeger AM, Cabiscol E, McKinstry SU et al. Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington's disease. Nature Communications. 2017 Feb 13;8. 14405. Available from, DOI: 10.1038/ncomms14405
Gomez-Pastor, Rocio ; Burchfiel, Eileen T. ; Neef, Daniel W. ; Jaeger, Alex M. ; Cabiscol, Elisa ; McKinstry, Spencer U. ; Doss, Argenia ; Aballay, Alejandro ; Lo, Donald C. ; Akimov, Sergey S. ; Ross, Christopher A. ; Eroglu, Cagla ; Thiele, Dennis J./ Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington's disease. In: Nature Communications. 2017 ; Vol. 8.
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