A huntingtin peptide inhibits polyQ-huntingtin associated defects.
A huntingtin peptide inhibits polyQ-huntingtin associated defects.
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DOI：
10.1371/journal.pone.0068775
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Maschat F
中科院分区：
文献类型：
--
作者：
Arribat Y;Bonneaud N;Talmat-Amar Y;Layalle S;Parmentier ML;Maschat F
亨廷顿病（HD）是由人亨廷顿蛋白（polyQ-hHtt）中的多聚谷氨酰胺束的异常扩张引起的。虽然这种突变的行为占主导地位，亨廷顿蛋白的功能丧失也有助于HD的发病机制。事实上，野生型亨廷顿蛋白对于polyQ-hHtt诱导的缺陷起保护作用。我们在这里讨论的问题是野生型亨廷顿蛋白的哪一部分负责这些保护特性。我们首先从HeLa细胞中的亨廷顿蛋白筛选肽，并鉴定了抑制polyQ-hHtt聚集的23 aa肽（P42）。P42是内源性亨廷顿蛋白的一部分，位于富含蛋白水解位点的区域内，该蛋白水解位点在发病过程中起关键作用。使用果蝇HD模型，我们测试了这种肽对聚集的保护特性，以及对不同polyQ-hHtt诱导的神经元表型的保护特性：眼变性（细胞死亡的指标），囊泡轴突运输的损伤，以及生理行为，如幼虫运动和成虫存活。总之，我们的研究结果证明了P42在整个动物体内的高保护特性。这些数据还证明了P42对亨廷顿病模型的特定作用，因为它对polyQ诱导的疾病的其他模型（例如脊髓小脑共济失调）没有影响。总之，我们的数据表明，P42，一个23 aa长的hHtt肽，发挥保护作用，相对于polyQ-hHtt聚集以及由polyQ-hHtt在体内诱导的细胞和行为功能障碍。我们的研究还证实了polyQ-hHtt聚集和神经元缺陷之间的相关性。最后，这些结果有力地表明了P42的治疗潜力，特异于亨廷顿病。
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.
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