Fondazione Santa Lucia IRCCS, 00143, Rome, Italy.
Dipartimento di Biologia, Università di Roma "Tor Vergata", Rome, Italy.
Sci Rep. 2017 May 17;7(1):2033. doi: 10.1038/s41598-017-02195-0.
Several of the identified genetic factors in Amyotrophic Lateral Sclerosis (ALS) point to dysfunction in RNA processing as a major pathogenic mechanism. However, whether a precise RNA pathway is particularly affected remains unknown. Evidence suggests that FUS, that is mutated in familial ALS, and SMN, the causative factor in Spinal Muscular Atrophy (SMA), cooperate to the same molecular pathway, i.e. regulation of alternative splicing, and that disturbances in SMN-regulated functions, either caused by depletion of SMN protein (as in the case of SMA) or by pathogenic interactions between FUS and SMN (as in the case of ALS) might be a common theme in both diseases. In this work, we followed these leads and tested their pathogenic relevance in vivo. FUS-associated ALS recapitulates, in transgenic mice, crucial molecular features that characterise mouse models of SMA, including defects in snRNPs distribution and in the alternative splicing of genes important for motor neurons. Notably, altering SMN levels by haploinsufficiency or overexpression does not impact the phenotypes of mouse or Drosophila models of FUS-mediated toxicity. Overall, these findings suggest that FUS and SMN functionally interact and that FUS may act downstream of SMN-regulated snRNP assembly in the regulation of alternative splicing and gene expression.
几种已确定的肌萎缩侧索硬化症 (ALS) 的遗传因素表明，RNA 处理功能障碍是主要的致病机制。然而，是否存在特定的 RNA 途径受到特别影响仍不清楚。有证据表明，在家族性 ALS 中发生突变的 FUS 和导致脊髓性肌萎缩症 (SMA) 的 SMN 因子，共同作用于同一分子途径，即可变剪接的调节，而 SMN 调节功能的紊乱，无论是由于 SMN 蛋白的耗竭（如在 SMA 的情况下）还是由于 FUS 和 SMN 之间的致病相互作用（如在 ALS 的情况下），可能是这两种疾病的共同主题。在这项工作中，我们遵循这些线索，并在体内测试它们的致病相关性。在转基因小鼠中，与 FUS 相关的 ALS 重现了 SMA 小鼠模型的关键分子特征，包括 snRNPs 分布缺陷和对运动神经元重要基因的可变剪接缺陷。值得注意的是，通过杂合不足或过表达改变 SMN 水平不会影响 FUS 介导的毒性的小鼠或果蝇模型的表型。总的来说，这些发现表明 FUS 和 SMN 具有功能相互作用，并且 FUS 可能在 SMN 调节的 snRNP 组装调节可变剪接和基因表达中起下游作用。
