title: A huntingtin peptide inhibits polyQ-huntingtin associated defects.
abstract: 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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Institut de Génomique Fonctionnelle (IGF), CNRS-UMR5203, INSERM-U661, University of Montpellier, Montpellier, France.
authors.forename: Yoan
authors.initials: Y
authors.lastname: Arribat
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bonneaud
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Talmat-Amar
authors.forename: Sophie
authors.initials: S
authors.lastname: Layalle
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Parmentier
authors.forename: Florence
authors.initials: F
authors.lastname: Maschat
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D005123:Eye / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007814:Larva / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009043:Motor Activity; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization / Q000187:drug effects; D021381:Protein Transport
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009842:Oligopeptides; D010455:Peptides; C097188:polyglutamine