Journal
BRAIN
Volume 139, Issue -, Pages 2891-2908Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/aww228
Keywords
spinocerebellar ataxia type 3; Machado-Joseph disease; therapeutics; drug screen; neurodegeneration
Categories
Funding
- Fundacao para a Ciencia e a Tecnologia (FCT) Portugal [SFRH/BPD/28560/2006]
- National Ataxia Foundation (NAF Research Fellowship Award)
- NIH [R01NS038712, R01NS086778]
- Mateus Ataxia Research Fund
- National Ataxia Foundation (NAF Pioneer SCA Translational Award)
- Fundação para a Ciência e a Tecnologia [SFRH/BPD/28560/2006] Funding Source: FCT
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No disease-modifying treatment exists for the fatal neurodegenerative polyglutamine disease known both as Machado- Joseph disease and spinocerebellar ataxia type 3. As a potential route to therapy, we identified small molecules that reduce levels of the mutant disease protein, ATXN3. Screens of a small molecule collection, including 1250 Food and Drug Administrationapproved drugs, in a novel cell- based assay, followed by secondary screens in brain slice cultures from transgenic mice expressing the human disease gene, identified the atypical antipsychotic aripiprazole as one of the hits. Aripiprazole increased longevity in a Drosophila model of Machado- Joseph disease and effectively reduced aggregated ATXN3 species in flies and in brains of transgenic mice treated for 10 days. The aripiprazole- mediated decrease in ATXN3 abundance may reflect a complex response culminating in the modulation of specific components of cellular protein homeostasis. Aripiprazole represents a potentially promising therapeutic drug for Machado- Joseph disease and possibly other neurological proteinopathies.
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