1. Unbiased screen identifies aripiprazole as a modulator of abundance of the polyglutamine disease protein, ataxin-3
- Author
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do Carmo Costa, Maria, Ashraf, Naila S, Fischer, Svetlana, Yang, Yemen, Schapka, Emily, Joshi, Gnanada, McQuade, Thomas J, Dharia, Rahil M, Dulchavsky, Mark, Ouyang, Michelle, Cook, David, Sun, Duxin, Larsen, Martha J, Gestwicki, Jason E, Todi, Sokol V, Ivanova, Magdalena I, and Paulson, Henry L
- Subjects
Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Neurodegenerative ,Brain Disorders ,Neurosciences ,Biotechnology ,Rare Diseases ,Genetics ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Neurological ,Animals ,Animals ,Genetically Modified ,Antipsychotic Agents ,Aripiprazole ,Ataxin-3 ,Brain ,Disease Models ,Animal ,Drosophila ,Drug Evaluation ,Preclinical ,Gene Expression Regulation ,HEK293 Cells ,Humans ,Machado-Joseph Disease ,Mice ,Mutant Proteins ,Nerve Tissue Proteins ,Organ Culture Techniques ,Peptides ,Piperidines ,Pyrans ,Pyrazoles ,spinocerebellar ataxia type 3 ,Machado-Joseph disease ,therapeutics ,drug screen ,neurodegeneration ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery ,Biomedical and clinical sciences ,Health sciences ,Psychology - 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.
- Published
- 2016