A huntingtin peptide inhibits polyQ-huntingtin associated defects

PLoS One. 2013 Jul 4;8(7):e68775. doi: 10.1371/journal.pone.0068775. Print 2013.


Background: Huntington's disease (HD) is caused by the abnormal expansion of the polyglutamine tract in the human Huntingtin protein (polyQ-hHtt). Although this mutation behaves dominantly, huntingtin loss of function also contributes to HD pathogenesis. Indeed, wild-type Huntingtin plays a protective role with respect to polyQ-hHtt induced defects.

Methodology/principal findings: The question that we addressed here is what part of the wild-type Huntingtin is responsible for these protective properties. We first screened peptides from the Huntingtin protein in HeLa cells and identified a 23 aa peptide (P42) that inhibits polyQ-hHtt aggregation. P42 is part of the endogenous Huntingtin protein and lies within a region rich in proteolytic sites that plays a critical role in the pathogenesis process. Using a Drosophila model of HD, we tested the protective properties of this peptide on aggregation, as well as on different polyQ-hHtt induced neuronal phenotypes: eye degeneration (an indicator of cell death), impairment of vesicular axonal trafficking, and physiological behaviors such as larval locomotion and adult survival. Together, our results demonstrate high protective properties for P42 in vivo, in whole animals. These data also demonstrate a specific role of P42 on Huntington's disease model, since it has no effect on other models of polyQ-induced diseases, such as spinocerebellar ataxias.

Conclusions/significance: Altogether our data show that P42, a 23 aa-long hHtt peptide, plays a protective role with respect to polyQ-hHtt aggregation as well as cellular and behavioral dysfunctions induced by polyQ-hHtt in vivo. Our study also confirms the correlation between polyQ-hHtt aggregation and neuronal defects. Finally, these results strongly suggest a therapeutic potential for P42, specific of Huntington's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Disease Models, Animal
  • Drosophila melanogaster / drug effects*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / growth & development
  • Drosophila melanogaster / metabolism
  • Eye / drug effects
  • Eye / metabolism
  • Eye / pathology
  • Female
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • Huntington Disease / pathology
  • Larva / drug effects*
  • Larva / genetics
  • Larva / growth & development
  • Larva / metabolism
  • Male
  • Molecular Sequence Data
  • Motor Activity
  • Mutation
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Oligopeptides / chemistry
  • Oligopeptides / isolation & purification
  • Oligopeptides / pharmacology*
  • Peptides / chemistry*
  • Peptides / metabolism
  • Protein Binding
  • Protein Multimerization / drug effects
  • Protein Transport


  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Oligopeptides
  • Peptides
  • polyglutamine

Grant support

Source of funding: CNRS (French National center of scientific research), “soutien au transfert” and ANR Emergence (Agence Nationale pour la Recherche). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.