小柯机器人

TDP-43缺失和ALS风险SNP导致UNC13A错误剪接和丢失，这一成果由英国伦敦大学学院Pietro Fratta和美国国立卫生研究院Michael E. Ward团队经过不懈努力而取得。这一研究成果于2022年2月23日发表在国际学术期刊《自然》上。

研究人员表明TDP-43缺失会导致UNC13A产生一个隐藏的外显子，导致无意突变介导的UNC13A蛋白衰变和丢失。与肌萎缩侧索硬化和额颞叶痴呆风险密切相关的UNC13A两种常见内含子多态性与TDP-43结合位点重叠。这些多态性在培养细胞以及患有这些疾病的患者大脑和脊髓中都增加了该隐藏外显子的产生。该研究结果证明了核TDP-43功能丧失与疾病之间存在遗传联系，揭示了UAC13A通过增加TDP-43来发挥调控功能的机制。进一步表明TDP-43蛋白可能是潜在的治疗靶点。

据介绍，UNC13A变体是调控突触功能的关键基因，该变体会增加肌萎缩侧索硬化症和额颞叶痴呆的发病风险，这两种相关神经退行性疾病是由RNA结合蛋白TDP-43错位导致的。

附：英文原文

Title: TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A

Author: Brown, Anna-Leigh, Wilkins, Oscar G., Keuss, Matthew J., Hill, Sarah E., Zanovello, Matteo, Lee, Weaverly Colleen, Bampton, Alexander, Lee, Flora C. Y., Masino, Laura, Qi, Yue A., Bryce-Smith, Sam, Gatt, Ariana, Hallegger, Martina, Fagegaltier, Delphine, Phatnani, Hemali, Newcombe, Jia, Gustavsson, Emil K., Seddighi, Sahba, Reyes, Joel F., Coon, Steven L., Ramos, Daniel, Schiavo, Giampietro, Fisher, Elizabeth M. C., Raj, Towfique, Secrier, Maria, Lashley, Tammaryn, Ule, Jernej, Buratti, Emanuele, Humphrey, Jack, Ward, Michael E., Fratta, Pietro

Issue&Volume: 2022-02-23

Abstract: Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia1,2,3, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-434,5. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.

DOI: 10.1038/s41586-022-04436-3

Source: https://www.nature.com/articles/s41586-022-04436-3

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/
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