Skip to main content

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

Publication ,  Journal Article
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 ...
Published in: Nat Commun
February 13, 2017

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

February 13, 2017

Volume

8

Start / End Page

14405

Location

England

Related Subject Headings

  • Rats
  • PC12 Cells
  • Neurons
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Male
  • Huntington Disease
  • Huntingtin Protein
  • Humans
  • Heat Shock Transcription Factors
 

Citation

APA
Chicago
ICMJE
MLA
NLM
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. Nat Commun, 8, 14405. https://doi.org/10.1038/ncomms14405
Gomez-Pastor, Rocio, Eileen T. Burchfiel, Daniel W. Neef, Alex M. Jaeger, Elisa Cabiscol, Spencer U. McKinstry, Argenia Doss, et al. “Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington's disease.Nat Commun 8 (February 13, 2017): 14405. https://doi.org/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. Nat Commun. 2017 Feb 13;8:14405.
Gomez-Pastor, Rocio, et al. “Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington's disease.Nat Commun, vol. 8, Feb. 2017, p. 14405. Pubmed, doi:10.1038/ncomms14405.
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. Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington's disease. Nat Commun. 2017 Feb 13;8:14405.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

February 13, 2017

Volume

8

Start / End Page

14405

Location

England

Related Subject Headings

  • Rats
  • PC12 Cells
  • Neurons
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Male
  • Huntington Disease
  • Huntingtin Protein
  • Humans
  • Heat Shock Transcription Factors