Unbiased screen identifies aripiprazole as a modulator of abundance of the polyglutamine disease protein, ataxin-3.
| Autor: | do Carmo Costa, Maria, Ashraf, Naila S., Fischer, Svetlana, Yemen Yang, Schapka, Emily, Joshi, Gnanada, McQuade, Thomas J., Dharia, Rahil M., Dulchavsky, Mark, Ouyang, Michelle, Cook, David, Duxin Sun, Larsen, Martha J., Gestwicki, Jason E., Todi, Sokol V., Ivanova, Magdalena I., Paulson, Henry L., Costa, Maria do Carmo, Yang, Yemen, Sun, Duxin |
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| Předmět: |
ARIPIPRAZOLE
POLYGLUTAMINE NERVE tissue proteins MEDICAL genetics HOMEOSTASIS PROTEIN metabolism ANTIPSYCHOTIC agents BRAIN metabolism ANIMAL experimentation BIOLOGICAL models BRAIN CEREBELLUM diseases DRUG design CLINICAL drug trials EPITHELIAL cells GENES HETEROCYCLIC compounds INSECTS RESEARCH methodology MICE PEPTIDES PIPERIDINE PROTEINS RESEARCH funding TISSUE culture TRANSGENIC animals PHARMACODYNAMICS |
| Zdroj: | Brain: A Journal of Neurology; Nov2016, Vol. 139 Issue 11, p2891-2908, 18p |
| Abstrakt: | 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. [ABSTRACT FROM AUTHOR] |
| Databáze: | Complementary Index |
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