title: Hsp104 suppresses polyglutamine-induced degeneration post onset in a drosophila MJD/SCA3 model.
abstract: There are no effective therapeutics that antagonize or reverse the protein-misfolding events underpinning polyglutamine (PolyQ) disorders, including Spinocerebellar Ataxia Type-3 (SCA3). Here, we augment the proteostasis network of Drosophila SCA3 models with Hsp104, a powerful protein disaggregase from yeast, which is bafflingly absent from metazoa. Hsp104 suppressed eye degeneration caused by a C-terminal ataxin-3 (MJD) fragment containing the pathogenic expanded PolyQ tract, but unexpectedly enhanced aggregation and toxicity of full-length pathogenic MJD. Hsp104 suppressed toxicity of MJD variants lacking a portion of the N-terminal deubiquitylase domain and full-length MJD variants unable to engage polyubiquitin, indicating that MJD-ubiquitin interactions hinder protective Hsp104 modalities. Importantly, in staging experiments, Hsp104 suppressed toxicity of a C-terminal MJD fragment when expressed after the onset of PolyQ-induced degeneration, whereas Hsp70 was ineffective. Thus, we establish the first disaggregase or chaperone treatment administered after the onset of pathogenic protein-induced degeneration that mitigates disease progression.
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America ; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America ; Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Mimi
authors.initials: M
authors.lastname: Cushman-Nick
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Bonini
authors.forename: James
authors.initials: J
authors.lastname: Shorter
mesh_terms: D000818:Animals; D000067699:Ataxin-3; D002460:Cell Line; D004195:Disease Models, Animal; D018450:Disease Progression; D004331:Drosophila melanogaster / Q000187:drug effects; D005128:Eye Diseases / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D017827:Machado-Joseph Disease / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010455:Peptides / Q000633:toxicity; D012097:Repressor Proteins / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D006360:Heat-Shock Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; C070972:HsP104 protein, S cerevisiae; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3
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