PloS one, 2013-07, Vol.8 (7), p.e68775-e68775
2013
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- Autor(en) / Beteiligte
- Titel
- A huntingtin peptide inhibits polyQ-huntingtin associated defects
- Ist Teil von
- PloS one, 2013-07, Vol.8 (7), p.e68775-e68775
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2013
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. 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. 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0068775Titel-ID: cdi_plos_journals_1394487928
- Format
- –
- Schlagworte
- Agglomeration, Amino Acid Sequence, Analysis, Animals, Apoptosis, Biology, Cell death, Correlation analysis, Defects, Degeneration, Disease Models, Animal, Drosophila, 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, Gene therapy, HeLa Cells, Human behavior, Human health and pathology, Humans, Huntingtin, Huntingtin Protein, Huntington Disease - genetics, Huntington Disease - metabolism, Huntington Disease - pathology, Huntington's disease, Huntingtons disease, In vivo methods and tests, Insects, Kinases, Larva - drug effects, Larva - genetics, Larva - growth & development, Larva - metabolism, Life Sciences, Locomotion, Male, Medicine, 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, Pathogenesis, Peptides, Peptides - chemistry, Peptides - metabolism, Phosphorylation, Polyglutamine, Polyglutamine diseases, Properties (attributes), Protein Binding, Protein Multimerization - drug effects, Protein Transport, Proteins, Proteolysis, Risk factors, Spinocerebellar ataxia, Trinucleotide repeat diseases