BIIB021, a synthetic Hsp90 inhibitor, induces mutant ataxin-1 degradation through the activation of heat shock factor 1
0301 basic medicine
0303 health sciences
Hot Temperature
Pyridines
Adenine
Nerve Tissue Proteins
3. Good health
DNA-Binding Proteins
Purkinje Cells
03 medical and health sciences
Heat Shock Transcription Factors
Cerebellum
Homeostasis
Humans
Spinocerebellar Ataxias
HSP90 Heat-Shock Proteins
Ataxin-1
Brain Stem
Transcription Factors
DOI:
10.1016/j.neuroscience.2016.03.064
Publication Date:
2016-04-04T06:01:30Z
AUTHORS (9)
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.
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CITATIONS (14)
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