title: BIIB021, a synthetic Hsp90 inhibitor, induces mutant ataxin-1 degradation through the activation of heat shock factor 1.
abstract: Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by the expansion of a polyglutamine (polyQ) tract in ataxin-1 (ATXN1). The pathological hallmarks of SCA1 are the loss of cerebellar Purkinje cells and neurons in the brainstem and the presence of nuclear aggregates containing the polyQ-expanded ATXN1 protein. Heat shock protein 90 (Hsp90) inhibitors have been shown to reduce polyQ-induced toxicity. This study was designed to examine the therapeutic effects of BIIB021, a purine-scaffold Hsp90 inhibitor, on the protein homeostasis of polyQ-expanded mutant ATXN1 in a cell culture model of SCA1. Our results demonstrated that BIIB021 activated heat shock factor 1 (HSF1) and suppressed the abnormal accumulation of ATXN1 and its toxicity. The pharmacological degradation of mutant ATXN1 via activated HSF1 was dependent on both the proteasome and autophagy systems. These findings indicate that HSF1 is a key molecule in the regulation of the protein homeostasis of the polyQ-expanded mutant ATXN1 and that Hsp90 has potential as a novel therapeutic target in patients with SCA1.
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Department of Neurology, University of Occupational and Environmental Health School of Medicine, Kitakyushu 807-8555, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Adachi
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Katsuno
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Sahashi
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Naohide
authors.initials: N
authors.lastname: Kondo
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Iida
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Genki
authors.initials: G
authors.lastname: Tohnai
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakatsuji
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Research Division of Dementia and Neurodegenerative Disease, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address: sobueg@med.nagoya-u.ac.jp.
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000067696:Ataxin-1 / Q000235:genetics / Q000378:metabolism*; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D006706:Homeostasis / Q000502:physiology; D006358:Hot Temperature; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011689:Purkinje Cells / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology*; D020754:Spinocerebellar Ataxias / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C521963:6-chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purin-2-ylamine; D000067696:Ataxin-1; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D009419:Nerve Tissue Proteins; D011725:Pyridines; D014157:Transcription Factors; D000225:Adenine
keywords: BIIB021; Hsp90 inhibitor; ataxin-1; heat shock factor 1; polyglutamine disease; spinocerebellar ataxia type 1