Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington's disease.
Rocio Gomez-PastorEileen T BurchfielDaniel W NeefAlex M JaegerElisa CabiscolSpencer U McKinstryArgenia DossAlejandro AballayDonald C LoSergey S AkimovChristopher A RossCagla ErogluDennis J ThielePublished in: Nature communications (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.
Keyphrases
- heat shock
- heat stress
- transcription factor
- heat shock protein
- mouse model
- cell death
- oxidative stress
- protein kinase
- binding protein
- protein protein
- wild type
- endothelial cells
- induced apoptosis
- gene expression
- cell cycle arrest
- functional connectivity
- resting state
- type diabetes
- spinal cord
- white matter
- metabolic syndrome
- genome wide
- dna methylation
- endoplasmic reticulum stress
- skeletal muscle
- molecular dynamics simulations
- adipose tissue
- cell proliferation
- stress induced
- spinal cord injury
- multiple sclerosis