title: Unbiased screen identifies aripiprazole as a modulator of abundance of the polyglutamine disease protein, ataxin-3.
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.
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Maria do Carmo
authors.initials: MDC
authors.lastname: Costa
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Naila S
authors.initials: NS
authors.lastname: Ashraf
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Fischer
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Yemen
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Schapka
authors.affiliation: Department of Pharmacology, Wayne State University, Detroit, MI, USA.
authors.forename: Gnanada
authors.initials: G
authors.lastname: Joshi
authors.affiliation: Center for Chemical Genomics, Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: McQuade
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Rahil M
authors.initials: RM
authors.lastname: Dharia
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Dulchavsky
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Ouyang
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: David
authors.initials: D
authors.lastname: Cook
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
authors.affiliation: Center for Chemical Genomics, Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Martha J
authors.initials: MJ
authors.lastname: Larsen
authors.affiliation: Department of Pharmaceutical Chemistry, Institute for Neurodegenerative Diseases, University of California at San Francisco, San Francisco, CA, USA.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
authors.affiliation: Department of Pharmacology, Wayne State University, Detroit, MI, USA.|Department of Neurology, Wayne State University, Detroit, MI, USA.
authors.forename: Sokol V
authors.initials: SV
authors.lastname: Todi
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.|Department of Biophysics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Magdalena I
authors.initials: MI
authors.lastname: Ivanova
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Henry L
authors.initials: HL
authors.lastname: Paulson
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D000068180:Aripiprazole / Q000627:therapeutic use*; D000067699:Ataxin-3 / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D004330:Drosophila; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D017827:Machado-Joseph Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D050505:Mutant Proteins / Q000187:drug effects* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009924:Organ Culture Techniques; D010455:Peptides / Q000235:genetics; D010880:Piperidines / Q000494:pharmacology; D011714:Pyrans / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D000095662:Polyether Polyketides
chemical_list: D014150:Antipsychotic Agents; D000068180:Aripiprazole; D000067699:Ataxin-3; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D010880:Piperidines; D011714:Pyrans; D011720:Pyrazoles; C097188:polyglutamine; C103505:AM 251; C010327:salinomycin; D000095662:Polyether Polyketides
keywords: Machado-Joseph disease; drug screen; neurodegeneration; spinocerebellar ataxia type 3; therapeutics