Hsp104 suppresses polyglutamine-induced degeneration post onset in a drosophila MJD/SCA3 model

PLoS Genet. 2013;9(9):e1003781. doi: 10.1371/journal.pgen.1003781. Epub 2013 Sep 5.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Ataxin-3
  • Cell Line
  • Disease Models, Animal
  • Disease Progression
  • Drosophila melanogaster / drug effects
  • Eye Diseases / chemically induced
  • Eye Diseases / genetics*
  • Eye Diseases / pathology
  • Heat-Shock Proteins / genetics*
  • Humans
  • Machado-Joseph Disease / genetics*
  • Machado-Joseph Disease / pathology
  • Machado-Joseph Disease / therapy
  • Nerve Tissue Proteins / genetics*
  • Nuclear Proteins / genetics*
  • Peptides / toxicity
  • Repressor Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / genetics*
  • Trinucleotide Repeat Expansion / genetics


  • Heat-Shock Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • Repressor Proteins
  • Saccharomyces cerevisiae Proteins
  • HsP104 protein, S cerevisiae
  • polyglutamine
  • ATXN3 protein, human
  • Ataxin-3