Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1
Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1
复制标题
DOI：
10.1073/pnas.1509744112
复制
发表时间：
2015-06-23
影响因子：
11.1
通讯作者：
Finkbeiner, Steven
中科院分区：
文献类型：
--
作者：
Barmada, Sami J.;Ju, Shulin;Finkbeiner, Steven
超过30%的肌萎缩侧索硬化症(ALS)患者表现出额颞部痴呆(FTD)的认知障碍，这表明这两种疾病的共同发病机制。与这一假设一致的是，在大多数ALS和FTD患者中发现了富含TDP43的神经元和神经胶质包涵体，TDP43和相关的RNA结合蛋白FUS的突变导致了家族性ALS和FTD。TDP43和FUS影响数千个转录本的剪接，在某些情况下触发无义介导的mRNA衰退(NMD)，这是一种高度保守的RNA降解途径。在这里，我们利用一个忠实的ALS和FTD的初级神经元模型来研究和表征人类上移码蛋白1(HUPF1)在这些疾病中的作用。hUPF1是一种RNA解旋酶，也是NMD的主要调节因子。我们发现hUPF1显著保护哺乳动物神经元免受TDP43和FUS相关的毒性。NMD的另一个重要成分hUPF2的表达也提高了存活率，而抑制NMD则阻止了hUPF1的拯救，表明hUPF1通过NMD发挥作用，提高存活率。这些研究强调了RNA代谢在ALS和FTD中的重要性，并确定了针对这些疾病的独特有效的治疗策略。
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.