Abstract
BackgroundHuntington’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 FindingsThe 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/SignificanceAltogether 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.
Highlights
In Humans, Huntington’s disease (HD) is an inherited neurodegenerative disorder belonging to the polyglutamine pathologies
Apart from the dominant function of polyQ-Human Huntingtin (hHtt), loss of function of the wild-type protein may contribute to the disease pathogenesis [25] [26] [27] [28] [20]. In support of this hypothesis, we previously showed that the ratio between the wild-type hHtt N-terminal fragment and the mutant polyQ-hHtt was critical for the onset of polyQ-hHtt associated-defects, in a Drosophila model of HD [20]
In order to identify the protective region of wild-type hHtt, we screened for peptides, within the human 0Q-hHtt548aa, that were able to prevent 138Q-hHtt171aa aggregation in HeLa cells
Summary
In Humans, Huntington’s disease (HD) is an inherited neurodegenerative disorder belonging to the polyglutamine pathologies. This disease is caused by an abnormal expansion of the CAG triplet in the huntingtin gene (htt). When the number of CAG repeats exceeds 35, the resulting mutant protein (polyQ-Htt) forms intracellular aggregates and causes neuronal degeneration, affecting the neurons of the striatum. Huntington’s disease (HD) is caused by the abnormal expansion of the polyglutamine tract in the human Huntingtin protein (polyQ-hHtt). This mutation behaves dominantly, huntingtin loss of function contributes to HD pathogenesis. Wild-type Huntingtin plays a protective role with respect to polyQ-hHtt induced defects
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