A Huntingtin Peptide Inhibits PolyQ-Huntingtin Associated Defects

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.

Huntingtin is required for ER-to-Golgi transport and for secretory vesicle fusion at the plasma membrane

“…The presence of one copy of wild-type huntingtin seems to be sufficient for maintaining secretion, at least in fibroblasts. In addition, the wild-type protein could also have a protective role with respect to the defects caused by expression of the mutant protein, as shown in a Drosophila model of HD ( Arribat et al, 2013 ). Moreover, the ratio of wild-type to mutant huntingtin might be crucial in determining cell fate ( Saleh et al, 2014 ) and, thus, strategies to reduce mutant huntingtin levels are being developed ( Stanek et al, 2014 ).…”

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

“…Recently, another peptide tested as a candidate‐based molecule, P42 (part of the endogenous HTT protein and lies within a region rich in proteolytic sites), was found to exert beneficial effects in a Drosophila HD model . To further test the beneficial effects of P42, Arribat et al.…”

The promises of neurodegenerative disease modeling

“…Another is the demonstration of the therapeutic potential of methylene blue that has been shown to reduced neurodegeneration and Hunttingtin aggregation in a fly HD model [53] and rescue heart defects in a fly model of Friedreich's ataxia [45]. The third one is the demonstration of the protective role against the aggregation of the polyglutamine disease protein of a short peptide from Huttingtin in an eye-toxicity test [54].…”