Interaction of the polyglutamine protein ataxin-3 with Rad23 regulates toxicity in Drosophila models of Spinocerebellar Ataxia Type 3

Hum Mol Genet. 2017 Apr 15;26(8):1419-1431. doi: 10.1093/hmg/ddx039.


Polyglutamine (polyQ) repeat expansion in the deubiquitinase ataxin-3 causes neurodegeneration in Spinocerebellar Ataxia Type 3 (SCA3), one of nine inherited, incurable diseases caused by similar mutations. Ataxin-3's degradation is inhibited by its binding to the proteasome shuttle Rad23 through ubiquitin-binding site 2 (UbS2). Disrupting this interaction decreases levels of ataxin-3. Since reducing levels of polyQ proteins can decrease their toxicity, we tested whether genetically modulating the ataxin-3-Rad23 interaction regulates its toxicity in Drosophila. We found that exogenous Rad23 increases the toxicity of pathogenic ataxin-3, coincident with increased levels of the disease protein. Conversely, reducing Rad23 levels alleviates toxicity in this SCA3 model. Unexpectedly, pathogenic ataxin-3 with a mutated Rad23-binding site at UbS2, despite being present at markedly lower levels, proved to be more pathogenic than a disease-causing counterpart with intact UbS2. Additional studies established that the increased toxicity upon mutating UbS2 stems from disrupting the autoprotective role that pathogenic ataxin-3 has against itself, which depends on the co-chaperone, DnaJ-1. Our data reveal a previously unrecognized balance between pathogenic and potentially therapeutic properties of the ataxin-3-Rad23 interaction; they highlight this interaction as critical for the toxicity of the SCA3 protein, and emphasize the importance of considering protein context when pursuing suppressive avenues.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Ataxin-3 / genetics*
  • Ataxin-3 / metabolism
  • Binding Sites
  • DNA Repair Enzymes / genetics*
  • DNA Repair Enzymes / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Drosophila melanogaster / genetics
  • Humans
  • Machado-Joseph Disease / genetics*
  • Machado-Joseph Disease / metabolism
  • Machado-Joseph Disease / pathology
  • Molecular Chaperones / genetics
  • Nerve Degeneration / genetics*
  • Nerve Degeneration / pathology
  • Peptides / genetics
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Ubiquitin / genetics


  • DNA-Binding Proteins
  • Molecular Chaperones
  • Peptides
  • Repressor Proteins
  • Ubiquitin
  • RAD23A protein, human
  • polyglutamine
  • ATXN3 protein, human
  • Ataxin-3
  • Proteasome Endopeptidase Complex
  • DNA Repair Enzymes