TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD.
TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD.
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DOI：
10.1126/science.aab0983
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发表时间：
2015-08-07
期刊：
影响因子：
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通讯作者：
Wong PC
中科院分区：
文献类型：
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作者：
Ling JP;Pletnikova O;Troncoso JC;Wong PC
胞浆中TDP-43的聚集，伴随其核清除，是肌萎缩侧索硬化和额颞叶痴呆（ALS-FTD）的一个关键的常见病理标志。然而，对这种rna结合蛋白（RBP）的有限理解阻碍了对TDP-43蛋白病致病机制的阐明。与调节保守外显子剪接的rbp相反，我们发现TDP-43抑制非保守外显子的剪接，维持内含子的完整性。当TDP-43从小鼠胚胎干细胞中消失时，这些隐外显子被剪接成信使rna，通常会破坏它们的翻译并促进无义介导的衰变。此外，强制抑制隐外显子可防止tdp -43缺陷细胞的细胞死亡。此外，ALS-FTD患者的隐外显子抑制受损，表明这种剪接缺陷可能是TDP-43蛋白病变的潜在基础。
Cytoplasmic aggregation of TDP-43, accompanied by its nuclear clearance, is a key common pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). However, a limited understanding of this RNA-binding protein (RBP) impedes the clarification of pathogenic mechanisms underlying TDP-43 proteinopathy. In contrast to RBPs that regulate splicing of conserved exons, we found that TDP-43 repressed the splicing of nonconserved cryptic exons, maintaining intron integrity. When TDP-43 was depleted from mouse embryonic stem cells, these cryptic exons were spliced into messenger RNAs, often disrupting their translation and promoting nonsense-mediated decay. Moreover, enforced repression of cryptic exons prevented cell death in TDP-43–deficient cells. Furthermore, repression of cryptic exons was impaired in ALS-FTD cases, suggesting that this splicing defect could potentially underlie TDP-43 proteinopathy.