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

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • February 13, 2017

Published In

Volume / Issue

  • 8 /

Start / End Page

  • 14405 -

PubMed ID

  • 28194040

Pubmed Central ID

  • 28194040

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/ncomms14405

Language

  • eng

Conference Location

  • England