小柯机器人

美国斯坦福大学Aaron D. Gitler和梅奥诊所Leonard Petrucelli团队合作发现TDP-43抑制额颞叶痴呆 (FTD)-肌萎缩侧索硬化症 (ALS)患者UNC13A基因中的隐藏外显子。该研究于2022年2月23日发表于国际学术期刊《自然》杂志上。

研究人员揭示了TDP-43抑制UNC13A中一个隐藏外显剪接的机制。人脑细胞核、神经元细胞系和源自诱导多能干细胞的运动神经元中TDP-43的缺失导致UNC13A mRNA中产生一个隐蔽的外显子剪接，并降低了UNC13A蛋白的表达。与人类FTD或ALS风险相关的最强变体位于含该隐蔽外显子的内含子中。研究表明，当TDP-43功能受损时候，它们会增加UNC13A中隐蔽外显子的剪接。总之，该数据提供了与FTD和ALS遗传风险最相关因素（UNC13A 遗传变异)与TDP-43功能丧失之间的直接功能联系。

据介绍，神经退行性疾病ALS和FTD的一个标志性病理特征是大脑和脊髓神经元细胞核RNA结合蛋白TDP-43的耗竭。TDP-43的主要功能是作为RNA剪接过程中隐含外显子的阻遏物。UNC13A中的单核苷酸多态性是人类全基因组关联研究中与FTD和ALS最相关的靶标之一，但这些变异如何增加疾病风险尚不清楚。

附：英文原文

Title: TDP-43 represses cryptic exon inclusion in the FTD–ALS gene UNC13A

Author: Ma, X. Rosa, Prudencio, Mercedes, Koike, Yuka, Vatsavayai, Sarat C., Kim, Garam, Harbinski, Fred, Briner, Adam, Rodriguez, Caitlin M., Guo, Caiwei, Akiyama, Tetsuya, Schmidt, H. Broder, Cummings, Beryl B., Wyatt, David W., Kurylo, Katherine, Miller, Georgiana, Mekhoubad, Shila, Sallee, Nathan, Mekonnen, Gemechu, Ganser, Laura, Rubien, Jack D., Jansen-West, Karen, Cook, Casey N., Pickles, Sarah, Oskarsson, Bjrn, Graff-Radford, Neill R., Boeve, Bradley F., Knopman, David S., Petersen, Ronald C., Dickson, Dennis W., Shorter, James, Myong, Sua, Green, Eric M., Seeley, William W., Petrucelli, Leonard, Gitler, Aaron D.

Issue&Volume: 2022-02-23

Abstract: A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord1. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing2,3,4. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies5,6, but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function.

DOI: 10.1038/s41586-022-04424-7

Source: https://www.nature.com/articles/s41586-022-04424-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html