Sharpe Joanne L, Harper Nikki S, Garner Duncan R, West Ryan J H
Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom.
Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield, United Kingdom.
Front Cell Neurosci. 2021 Oct 21;15:770937. doi: 10.3389/fncel.2021.770937. eCollection 2021.
An intronic hexanucleotide (GGGGCC) expansion in the gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In the decade following its discovery, much progress has been made in enhancing our understanding of how it precipitates disease. Both loss of function caused by reduced transcript levels, and gain of function mechanisms, triggered by the production of repetitive sense and antisense RNA and dipeptide repeat proteins, are thought to contribute to the toxicity. models, with their unrivaled genetic tractability and short lifespan, have played a key role in developing our understanding of -related FTD/ALS. There is no homolog in fly, and although this precludes investigations into loss of function toxicity, it is useful for elucidating mechanisms underpinning gain of function toxicity. To date there are a range of models, encompassing different aspects of gain of function toxicity. In addition to pure repeat transgenes, which produce both repeat RNA and dipeptide repeat proteins (DPRs), RNA only models and DPR models have been generated to unpick the individual contributions of RNA and each dipeptide repeat protein to toxicity. In this review, we discuss how models have shaped our understanding of gain of function toxicity, and address opportunities to utilize these models for further research.
基因中的内含子六核苷酸（GGGGCC）扩增是额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS）最常见的遗传病因。在其发现后的十年里，我们在加深对其如何引发疾病的理解方面取得了很大进展。由转录本水平降低导致的功能丧失以及由重复的正义和反义RNA及二肽重复蛋白的产生所引发的功能获得机制，都被认为与毒性有关。果蝇模型凭借其无与伦比的遗传易处理性和较短的寿命，在我们对与相关的FTD/ALS的理解发展中发挥了关键作用。果蝇中没有同源物，虽然这排除了对功能丧失毒性的研究，但它有助于阐明功能获得毒性的潜在机制。迄今为止，有一系列果蝇模型，涵盖了功能获得毒性的不同方面。除了产生重复RNA和二肽重复蛋白（DPRs）的纯重复转基因外，还产生了仅RNA模型和DPR模型，以剖析RNA和每种二肽重复蛋白对毒性的各自贡献。在这篇综述中，我们讨论了果蝇模型如何塑造了我们对功能获得毒性的理解，并探讨了利用这些模型进行进一步研究的机会。
