技术专题

近日，来自美国密歇根大学的研究人员发现一条可靶向治疗肌萎缩侧索硬化（ALS）的分子机制，通过增加一种关键蛋白的表达能够成功地阻止肌肉细胞死亡，对于遗传性和散发型的ALS治疗都具有重要启示。

近两年互联网上兴起"冰桶挑战"关爱"渐冻人"行动，旨在帮助大家了解罕见病，走进"渐冻人"生活。那究竟什么是"渐冻人"呢？"渐冻人"是指患有肌萎缩侧索硬化疾病（ALS）的病人，而ALS是一种神经退行性紊乱疾病，在上运动神经元和下运动神经元损伤之后，会导致包括四肢，躯干，胸部腹部等部位的肌肉逐渐无力和萎缩，使病人失去运动能力最终导致瘫痪甚至死亡。

在该项研究中，研究人员发现一种叫作hUPF1的蛋白能够调节ALS疾病模型的神经退行性过程。之前一些研究已经发现hUPF1可以作为治疗ALS的潜在治疗八点发挥作用，但其是否可以阻止细胞死亡仍不清楚。在该项研究中，研究人员通过一种ALS细胞模型检测了hUPF1保护细胞避免发生神经退行性过程的能力，结果发现通过过表达hUPF1能够增加神经元细胞的存活，而对机制进一步研究，研究人员发现hUPF1能够通过一种叫作无义介导的mRNA降解过程（NMD）执行细胞内监视功能，一旦出现非正常的mRNA，可通过NMD过程对mRNA进行降解，避免翻译出功能紊乱的TDP43蛋白，保证具有正常功能的tdp43蛋白水平处于一种稳定状态，从而维持神经元细胞存活。

研究人员最后提到，他们希望能够利用NMD过程开发靶向治疗药物，影响TDP43蛋白水平，从而实现对神经元的保护作用，最终实现治疗ALS。

Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1

Sami J. Barmadaa,1, Shulin Jub, Arpana Arjunc, Anthony Batarsec, Hilary C. Archbolda, Daniel Peisacha, Xingli Lia, Yuxi Zhanga, Elizabeth M. H. Tanka, Haiyan Qiud, Eric J. Huangd, Dagmar Ringee, Gregory A. Petskoe,f,1, and Steven Finkbeiner

Over 30% of patients with amyotrophic lateral sclerosis (ALS) exhibit cognitive deficits indicative of frontotemporal dementia (FTD), suggesting a common pathogenesis for both diseases. Consistent with this hypothesis, neuronal and glial inclusions rich in TDP43, an essential RNA-binding protein, are found in the majority of those with ALS and FTD, and mutations in TDP43 and a related RNA-binding protein, FUS, cause familial ALS and FTD. TDP43 and FUS affect the splicing of thousands of transcripts, in some cases triggering nonsense-mediated mRNA decay (NMD), a highly conserved RNA degradation pathway. Here, we take advantage of a faithful primary neuronal model of ALS and FTD to investigate and characterize the role of human up-frameshift protein 1 (hUPF1), an RNA helicase and master regulator of NMD, in these disorders. We show that hUPF1 significantly protects mammalian neurons from both TDP43- and FUS-related toxicity. Expression of hUPF2, another essential component of NMD, also improves survival, whereas inhibiting NMD prevents rescue by hUPF1, suggesting that hUPF1 acts through NMD to enhance survival. These studies emphasize the importance of RNA metabolism in ALS and FTD, and identify a uniquely effective therapeutic strategy for these disorders.