| First Author | Gomez-Pastor R | Year | 2017 |
| Journal | Nat Commun | Volume | 8 |
| Pages | 14405 | PubMed ID | 28194040 |
| Mgi Jnum | J:243965 | Mgi Id | MGI:5912744 |
| Doi | 10.1038/ncomms14405 | Citation | Gomez-Pastor R, et al. (2017) Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington's disease. Nat Commun 8:14405 |
| abstractText | 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 CK2alpha' kinase and Fbxw7 E3 ligase levels, phosphorylating HSF1 and promoting its proteasomal degradation. An HD mouse model heterozygous for CK2alpha' 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 CK2alpha'. These results reveal a pathway that could be modulated to prevent neuronal dysfunction and muscle wasting caused by protein misfolding in HD. |
