title: Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington's disease.
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.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina 27710, USA.
authors.forename: Rocio
authors.initials: R
authors.lastname: Gomez-Pastor
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina 27710, USA.|Department of Biochemistry, Duke University School of Medicine, Durham, North Carolina 27710, USA.
authors.forename: Eileen T
authors.initials: ET
authors.lastname: Burchfiel
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina 27710, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Neef
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina 27710, USA.
authors.forename: Alex M
authors.initials: AM
authors.lastname: Jaeger
authors.affiliation: Departament de Ciencies Mediques Basiques, IRB Lleida, Universitat de Lleida, Lleida 25008, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Cabiscol
authors.affiliation: Department of Cell Biology, Duke University School of Medicine, Durham, North Carolina 27710, USA.
authors.forename: Spencer U
authors.identifier: 0000-0002-3704-8919
authors.initials: SU
authors.lastname: McKinstry
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina 27710, USA.
authors.forename: Argenia
authors.initials: A
authors.lastname: Doss
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina 27710, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Aballay
authors.affiliation: Department of Neurobiology, Duke University School of Medicine, Durham, North Carolina 27710, USA.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Lo
authors.affiliation: Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Sergey S
authors.initials: SS
authors.lastname: Akimov
authors.affiliation: Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.affiliation: Department of Cell Biology, Duke University School of Medicine, Durham, North Carolina 27710, USA.|Department of Neurobiology, Duke University School of Medicine, Durham, North Carolina 27710, USA.
authors.forename: Cagla
authors.initials: C
authors.lastname: Eroglu
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina 27710, USA.|Department of Biochemistry, Duke University School of Medicine, Durham, North Carolina 27710, USA.|Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina 27710, USA.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Thiele
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D057809:HEK293 Cells; D000076249:Heat Shock Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics / Q000378:metabolism; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats
chemical_list: C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D000071058:Huntingtin Protein