Novel polyglutamine model uncouples proteotoxicity from aging

PLoS One. 2014 May 9;9(5):e96835. doi: 10.1371/journal.pone.0096835. eCollection 2014.


Polyglutamine expansions in certain proteins are the genetic determinants for nine distinct progressive neurodegenerative disorders and resultant age-related dementia. In these cases, neurodegeneration is due to the aggregation propensity and resultant toxic properties of the polyglutamine-containing proteins. We are interested in elucidating the underlying mechanisms of toxicity of the protein ataxin-3, in which a polyglutamine expansion is the genetic determinant for Machado-Joseph Disease (MJD), also referred to as spinocerebellar ataxia 3 (SCA3). To this end, we have developed a novel model for ataxin-3 protein aggregation, by expressing a disease-related polyglutamine-containing fragment of ataxin-3 in the genetically tractable body wall muscle cells of the model system C. elegans. Here, we demonstrate that this ataxin-3 fragment aggregates in a polyQ length-dependent manner in C. elegans muscle cells and that this aggregation is associated with cellular dysfunction. However, surprisingly, this aggregation and resultant toxicity was not influenced by aging. This is in contrast to polyglutamine peptides alone whose aggregation/toxicity is highly dependent on age. Thus, the data presented here not only describe a new polyglutamine model, but also suggest that protein context likely influences the cellular interactions of the polyglutamine-containing protein and thereby modulates its toxic properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism*
  • Aging / physiology
  • Amino Acid Sequence
  • Animals
  • Ataxin-3
  • Caenorhabditis elegans / cytology
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans / physiology
  • Heat-Shock Response
  • Humans
  • Molecular Sequence Data
  • Muscles / cytology
  • Muscles / metabolism
  • Nerve Tissue Proteins / chemistry*
  • Nuclear Proteins / chemistry*
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptides / metabolism*
  • Protein Aggregation, Pathological*
  • Protein Folding
  • Repressor Proteins / chemistry*


  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptide Fragments
  • Peptides
  • Repressor Proteins
  • polyglutamine
  • ATXN3 protein, human
  • Ataxin-3

Grant support

There was no external funding for this work. All funding was provided by start-up funds from the University of the South including the Office of the Dean of the College of Arts and Sciences, and Conduff. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.