期刊
NEUROSCIENCE
卷 327, 期 -, 页码 20-31出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2016.03.064
关键词
spinocerebellar ataxia type 1; ataxin-1; Hsp90 inhibitor; BIIB021; heat shock factor 1; polyglutamine disease
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan [26293206, 26293207, 26670440, 2667043, 15K15337]
- Japan Agency for Medical Research and Development (AMED) [15ek0109048]
- Grants-in-Aid for Scientific Research [26670440, 26293206, 15K15337, 26293207, 26860665, 15K19482] Funding Source: KAKEN
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. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
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