title: The deubiquitinase ataxin-3 requires Rad23 and DnaJ-1 for its neuroprotective role in Drosophila melanogaster.
abstract: Ataxin-3 is a deubiquitinase and polyglutamine (polyQ) disease protein with a protective role in Drosophila melanogaster models of neurodegeneration. In the fruit fly, wild-type ataxin-3 suppresses toxicity from several polyQ disease proteins, including a pathogenic version of itself that causes spinocerebellar ataxia type 3 and pathogenic huntingtin, which causes Huntington's disease. The molecular partners of ataxin-3 in this protective function are unclear. Here, we report that ataxin-3 requires its direct interaction with the ubiquitin-binding and proteasome-associated protein, Rad23 (known as hHR23A/B in mammals) in order to suppress toxicity from polyQ species in Drosophila. According to additional studies, ataxin-3 does not rely on autophagy or the proteasome to suppress polyQ-dependent toxicity in fly eyes. Instead this deubiquitinase, through its interaction with Rad23, leads to increased protein levels of the co-chaperone DnaJ-1 and depends on it to protect against degeneration. Through DnaJ-1, our data connect ataxin-3 and Rad23 to protective processes involved with protein folding rather than increased turnover of toxic polyQ species.
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Wei-Ling
authors.initials: WL
authors.lastname: Tsou
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Ouyang
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Ryan R
authors.initials: RR
authors.lastname: Hosking
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Joanna R
authors.initials: JR
authors.lastname: Sutton
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Blount
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA; Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Burr
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA; Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI 48201, USA; Department of Neurology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Sokol V
authors.initials: SV
authors.lastname: Todi
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000067699:Ataxin-3 / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D000066829:Neuroprotection / Q000502:physiology*; D010455:Peptides; D017510:Protein Folding
chemical_list: D004268:DNA-Binding Proteins; C494637:DnaJ-1 protein, Drosophila; D029721:Drosophila Proteins; D050956:HSP40 Heat-Shock Proteins; D010455:Peptides; C097188:polyglutamine; D000067699:Ataxin-3; D045643:DNA Repair Enzymes
keywords: Ataxin-3; Chaperone; Deubiquitinase; Drosophila; Machado–Joseph disease; Polyglutamine; Ubiquitin