Mechanisms of C9orf72-associated dipeptide toxicity

 描述(申请人提供)：C9orf72基因中的六核苷酸扩增导致约50%的家族性ALS病例。这种扩张导致疾病的机制(S)尚不清楚。目前解释疾病机制的假说包括单倍体功能不全和功能获得RNA和/或蛋白质毒性。尽管它存在于内含子中，但导致扩张的疾病被翻译成来自正义链和反义链的多个阅读框架中的蛋白质，从而产生五种不同的二肽蛋白质。这些二肽中的每一个都在ALS患者的样本中被特异性地检测到。最近的几项研究以及我们自己的数据表明，精氨酸二肽通过未知的机制显示出显著的神经毒性。在这里，我们将使用线虫的基因筛选，然后在果蝇和哺乳动物细胞中进行验证，以确定这些机制。我们的研究将为二肽参与和杀死运动神经元的途径提供重要的新见解，并可能为治疗这种目前无法治愈的疾病确定新的危险因素和新的治疗靶点。

 DESCRIPTION (provided by applicant): Hexanucleotide expansions in the C9orf72 gene cause ~50% of all familial ALS cases. The mechanism(s) by which this expansion causes disease are not known. Current hypotheses to explain the disease mechanism include haploinsufficiency and gain-of-function RNA and/or protein toxicity. Despite its presence in an intron, the disease causing expansion is translated into protein in multiple reading frames from both the sense and anti-sense strands to produce five distinct dipeptide proteins. Expression of each of these dipeptides has been specifically detected in ALS patient samples. Several recent studies, as well as our own data, show that the arginine dipeptides exhibit substantial neurotoxicity through unknown mechanisms. Here, we will use genetic screening in C. elegans, followed by validation in Drosophila and mammalian cells, to identify these mechanisms. Our studies will provide significant new insights into the pathways by which dipeptides engages and kill motor neurons and may identify novel risk factors and new therapeutic targets for treating this currently incurable disease