FUS ALS-causative mutations impact FUS autoregulation and the processing of RNA-binding proteins through intron retention-猫眼课题宝

DOI：

10.1101/567735

发表时间：

2019-03

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

J. Humphrey;N. Birsa;Carmelo Milioto;D. Robaldo;A. B. Eberle;Rahel Kräuchi;Matthew Bentham;A. Ule;Seth Jarvis;C. Bodo;M. G. Garone;A. Devoy;A. Rosa;I. Bozzoni;E. Fisher;M. Ruepp;O. Mühlemann;G. Schiavo;A. Isaacs;V. Plagnol;P. Fratta

RNA结合蛋白FUS的突变导致肌萎缩侧索硬化症（ALS），这是一种破坏性的神经退行性疾病，其中运动神经元的丧失诱导进行性虚弱和呼吸衰竭死亡，通常仅在发病后3-5年。FUS在RNA代谢的许多方面发挥作用，包括mRNA剪接。然而，ALS致病突变对剪接的影响尚未完全表征，因为大多数疾病模型都是基于FUS过表达，其本身改变了其RNA加工功能。为了克服这一点，我们和其他人最近创建了敲入模型，并在FUS敲除的同时生成了FUS突变体的高深度RNA测序数据。我们将三个独立的数据集与联合建模方法相结合，使我们能够将突变引起的变化与真正的功能丧失进行比较。我们发现，FUS ALS突变诱导表达和剪接功能的广泛丧失，对RNA结合蛋白具有优先作用。突变FUS通过RNA结合诱导内含子保留的变化，我们确定了一个内含子保留事件FUS本身，这是与其自身调节。FUS调节的改变与疾病有关，有趣的是，我们发现FUS自身调节不仅被FUS突变改变，而且在ALS的其他遗传形式中也被改变，包括由TDP-43，VCP和SOD 1突变引起的，支持多个ALS基因在调节网络中相互作用的概念。

Mutations in the RNA-binding protein FUS cause amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease in which the loss of motor neurons induces progressive weakness and death from respiratory failure, typically only 3-5 years after onset. FUS plays a role in numerous aspects of RNA metabolism, including mRNA splicing. However, the impact of ALS-causative mutations on splicing has not been fully characterised, as most disease models have been based on FUS overexpression, which in itself alters its RNA processing functions. To overcome this, we and others have recently created knock-in models, and have generated high depth RNA-sequencing data on FUS mutants in parallel to FUS knockout. We combined three independent datasets with a joint modelling approach, allowing us to compare the mutation-induced changes to genuine loss of function. We find that FUS ALS-mutations induce a widespread loss of function on expression and splicing, with a preferential effect on RNA binding proteins. Mutant FUS induces intron retention changes through RNA binding, and we identify an intron retention event in FUS itself that is associated with its autoregulation. Altered FUS regulation has been linked to disease, and intriguingly, we find FUS autoregulation to be altered not only by FUS mutations, but also in other genetic forms of ALS, including those caused by TDP-43, VCP and SOD1 mutations, supporting the concept that multiple ALS genes interact in a regulatory network.

FUS ALS-causative mutations impact FUS autoregulation and the processing of RNA-binding proteins through intron retention

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