TDP-43 mutations increase HNRNP A1-7B through gain of splicing function
TDP-43 mutations increase HNRNP A1-7B through gain of splicing function
复制标题
TDP-43 突变通过获得剪接功能增加 HNRNP A1-7B
作者：
Sivakumar P
在最近的一项调查中，Deshaies和同事（2018）确定了HNRNP A1- 7 B，RNA结合蛋白（RBP）HNRNP A1的亚型，存在于死后肌萎缩侧索硬化症（ALS）脊髓运动神经元内含物中。HNRNP A1是ALS中的重要参与者，因为其低复杂性结构域（LCD）中的突变可以是该疾病的病因（Kim et al.，2013年）。有趣的是，Deshaies等人描述的同种型包括外显子7 B，其产生LCD的52个氨基酸的延伸，指出这种选择性剪接事件与神经元蛋白质聚集之间的联系。作者进一步指出，RBP TDP-43的缺失可能影响这种剪接事件，并导致易聚集7 B亚型的增加。TDP-43在> 95%的ALS病例中异常错误定位，并且当突变时可引起ALS（Harrison和Shorter，2017）JDP-43结合RNA，优先在UG重复序列处结合，并且参与可变剪接（Buratti和Baralle，2001）。重要的是，它的活性是非常剂量敏感的，使得生理表达成为研究TDP-43突变对剪接影响的必要条件。最近，我们和其他人已经发表了一系列新的生理TDP-43小鼠突变模型的等位基因，并显示C-末端突变诱导RNA剪接功能获得性（Fratta et al.，2018;白色等人，2018年）。来调查
Sir, In a recent investigation Deshaies and colleagues (2018) identified HNRNP A1-7B, an isoform of the RNA binding protein (RBP) HNRNP A1, as present in post-mortem amyotrophic lateral sclerosis (ALS) spinal motor neuron inclusions. HNRNP A1 is an important player in ALS, as mutations in its low complexity domain (LCD) can be causative for the disease (Kim et al., 2013). Intriguingly, the isoform described by Deshaies et al. includes exon 7B, which produces an extension of the LCD by 52 amino acids, pointing to a link between this alternative splicing event and neuronal protein aggregation. The authors further suggest that loss of RBP TDP-43 can influence this splicing event and result in an increase of the aggregation-prone 7B isoform. TDP-43 is abnormally mislocalized in> 95% of ALS cases and, when mutated, can cause ALS (Harrison and Shorter, 2017).TDP-43 binds RNA, preferentially at UG repeats, and is involved in alternative splicing (Buratti and Baralle, 2001). Importantly, its activity is extremely dosage-sensitive, making physiological expression an essential condition for studying the effect of TDP-43 mutations on splicing. Recently, we and others have published an allelic series of novel physiological TDP-43 mouse mutant models and shown that C-terminal mutations induce RNA splicing gain-of-function (Fratta et al., 2018; White et al., 2018). To investigate the link between