Comparative Analysis of Mutant Huntingtin Binding Partners in Yeast Species

Sci Rep. 2018 Jun 22;8(1):9554. doi: 10.1038/s41598-018-27900-5.


Huntington's disease is caused by the pathological expansion of a polyglutamine (polyQ) stretch in Huntingtin (Htt), but the molecular mechanisms by which polyQ expansion in Htt causes toxicity in selective neuronal populations remain poorly understood. Interestingly, heterologous expression of expanded polyQ Htt is toxic in Saccharomyces cerevisiae cells, but has no effect in Schizosaccharomyces pombe, a related yeast species possessing very few endogenous polyQ or Q/N-rich proteins. Here, we used a comprehensive and unbiased mass spectrometric approach to identify proteins that bind Htt in a length-dependent manner in both species. Analysis of the expanded polyQ-associated proteins reveals marked enrichment of proteins that are localized to and play functional roles in nucleoli and mitochondria in S. cerevisiae, but not in S. pombe. Moreover, expanded polyQ Htt appears to interact preferentially with endogenous polyQ and Q/N-rich proteins, which are rare in S. pombe, as well as proteins containing coiled-coil motifs in S. cerevisiae. Taken together, these results suggest that polyQ expansion of Htt may cause cellular toxicity in S. cerevisiae by sequestering endogenous polyQ and Q/N-rich proteins, particularly within nucleoli and mitochondria.

Publication types

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

MeSH terms

  • Computational Biology
  • Huntingtin Protein / chemistry
  • Huntingtin Protein / genetics*
  • Huntingtin Protein / metabolism*
  • Mutation*
  • Peptides
  • Phenotype
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Schizosaccharomyces / genetics
  • Schizosaccharomyces / metabolism*
  • Schizosaccharomyces pombe Proteins / metabolism*
  • Substrate Specificity


  • Huntingtin Protein
  • Peptides
  • Saccharomyces cerevisiae Proteins
  • Schizosaccharomyces pombe Proteins
  • polyglutamine