International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
Adv Exp Med Biol. 2021;1281:243-267. doi: 10.1007/978-3-030-51140-1_15.
Following the discovery of TDP-43 and FUS involvement in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD), the major challenge in the field has been to understand their physiological functions, both in normal and disease conditions. The hope is that this knowledge will improve our understanding of disease and lead to the development of effective therapeutic options. Initially, the focus has been directed at characterizing the role of these proteins in the control of RNA metabolism, because the main function of TDP-43 and FUS is to bind coding and noncoding RNAs to regulate their life cycle within cells. As a result, we now have an in-depth picture of the alterations that occur in RNA metabolism following their aggregation in various ALS/FTLD models and, to a somewhat lesser extent, in patients' brains. In parallel, progress has been made with regard to understanding how aggregation of these proteins occurs in neurons, how it can spread in different brain regions, and how these changes affect various metabolic cellular pathways to result in neuronal death. The aim of this chapter will be to provide a general overview of the trending topics in TDP-43 and FUS investigations and to highlight what might represent the most promising avenues of research in the years to come.
继 TDP-43 和 FUS 被发现与肌萎缩性侧索硬化症（ALS）和额颞叶痴呆（FTLD）有关后，该领域的主要挑战一直是了解它们在正常和疾病状态下的生理功能。希望这一知识能增进我们对疾病的理解，并能开发出有效的治疗方法。最初，研究的重点是描述这些蛋白在 RNA 代谢调控中的作用，因为 TDP-43 和 FUS 的主要功能是结合编码和非编码 RNA，以调节它们在细胞内的生命周期。因此，我们现在对在各种 ALS/FTLD 模型中这些蛋白聚集后发生的 RNA 代谢改变有了深入的了解，在一定程度上，我们对患者大脑中的改变也有了了解。与此同时，我们在理解这些蛋白如何在神经元中聚集、如何在不同的脑区扩散以及这些变化如何影响各种代谢细胞途径导致神经元死亡方面也取得了进展。本章的目的是对 TDP-43 和 FUS 研究中的热门话题进行概述，并强调未来几年最有希望的研究方向。
