Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
J Neurol. 2013 Nov;260(11):2917-27. doi: 10.1007/s00415-013-7112-y. Epub 2013 Oct 2.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting both upper and lower motor neurons. The prognosis for ALS is extremely poor, but there is a limited course of treatment with only one approved medication. A most striking recent discovery is that TDP-43 is identified as a key molecule that is associated with both sporadic and familial forms of ALS. TDP-43 is not only a pathological hallmark, but also a genetic cause for ALS. Subsequently, a number of ALS-causative genes have been found. Above all, the RNA-binding protein, such as FUS, TAF15, EWSR1 and hnRNPA1, have structural and functional similarities to TDP-43, and physiological functions of some molecules, including VCP, UBQLN2, OPTN, FIG4 and SQSTM1, are involved in a protein degradation system. These discoveries provide valuable insight into the pathogenesis of ALS, and open doors for developing an effective disease-modifying therapy.
肌萎缩侧索硬化症（ALS）是一种毁灭性的神经退行性疾病，影响上下运动神经元。ALS 的预后极差，但目前只有一种经过批准的药物可以进行有限的治疗。最近一个引人注目的发现是 TDP-43 被确定为与散发性和家族性 ALS 都相关的关键分子。TDP-43 不仅是一种病理标志物，也是 ALS 的遗传原因。随后，发现了许多 ALS 致病基因。最重要的是，RNA 结合蛋白，如 FUS、TAF15、EWSR1 和 hnRNPA1，与 TDP-43 在结构和功能上具有相似性，而包括 VCP、UBQLN2、OPTN、FIG4 和 SQSTM1 在内的一些分子的生理功能涉及到一个蛋白质降解系统。这些发现为 ALS 的发病机制提供了有价值的见解，并为开发有效的疾病修饰治疗方法开辟了道路。
