Journal article
Unbiased screen identifies aripiprazole as a modulator of abundance of the polyglutamine disease protein, ataxin-3
Brain (London, England : 1878), Vol.139(11), pp.2891-2908
11/01/2016
DOI: 10.1093/brain/aww228
PMCID: PMC5840879
PMID: 27645800
Abstract
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 Administration-approved 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.
Details
- Title: Subtitle
- Unbiased screen identifies aripiprazole as a modulator of abundance of the polyglutamine disease protein, ataxin-3
- Creators
- Maria do Carmo Costa - University of Michigan–Ann ArborNaila S Ashraf - University of Michigan–Ann ArborSvetlana Fischer - University of Michigan–Ann ArborYemen Yang - University of Michigan–Ann ArborEmily Schapka - University of Michigan–Ann ArborGnanada Joshi - Wayne State UniversityThomas J McQuade - University of Michigan–Ann ArborRahil M Dharia - University of Michigan–Ann ArborMark Dulchavsky - University of Michigan–Ann ArborMichelle Ouyang - University of Michigan–Ann ArborDavid Cook - University of Michigan–Ann ArborDuxin Sun - University of Michigan–Ann ArborMartha J Larsen - University of Michigan–Ann ArborJason E Gestwicki - Department of Pharmaceutical Chemistry, Institute for Neurodegenerative Diseases, University of California at San Francisco, San Francisco, CA, USASokol V Todi - Wayne State UniversityMagdalena I Ivanova - University of Michigan–Ann ArborHenry L Paulson - University of Michigan–Ann Arbor
- Resource Type
- Journal article
- Publication Details
- Brain (London, England : 1878), Vol.139(11), pp.2891-2908
- DOI
- 10.1093/brain/aww228
- PMID
- 27645800
- PMCID
- PMC5840879
- ISSN
- 0006-8950
- eISSN
- 1460-2156
- Grant note
- R01 NS086778 / NINDS NIH HHS
- Language
- English
- Date published
- 11/01/2016
- Academic Unit
- Radiology
- Record Identifier
- 9984697627902771
Metrics
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