Cortical hyperexcitability and mislocalization of the RNA-binding protein TDP43 are highly conserved features in amyotrophic lateral sclerosis (ALS). Nevertheless, the relationship between these phenomena remains poorly defined. Here, we showed that hyperexcitability recapitulates TDP43 pathology by upregulating shortened TDP43 (sTDP43) splice isoforms. These truncated isoforms accumulated in the cytoplasm and formed insoluble inclusions that sequestered full-length TDP43 via preserved N-terminal interactions. Consistent with these findings, sTDP43 overexpression was toxic to mammalian neurons, suggesting neurodegeneration arising from complementary gain- and loss-of-function mechanisms. In humans and mice, sTDP43 transcripts were enriched in vulnerable motor neurons, and we observed a striking accumulation of sTDP43 within neurons and glia of ALS patients. Collectively, these studies uncover a pathogenic role for alternative TDP43 isoforms in ALS, and implicate sTDP43 as a key contributor to the susceptibility of motor neurons in this disorder.

中文翻译：

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神经元活动过度上调的缩短的TDP43亚型驱动ALS中的TDP43病理

皮质过度兴奋和RNA结合蛋白TDP43的错位是肌萎缩性侧索硬化症（ALS）中高度保守的特征。但是，这些现象之间的关系仍然定义不清。在这里，我们表明过度兴奋通过上调缩短的TDP43（sTDP43）剪接异构体来概括TDP43病理。这些截短的同工型积累在细胞质中，形成不溶性包裹体，通过保留的N末端相互作用将全长TDP43隔离。与这些发现一致，sTDP43的过表达对哺乳动物神经元有毒性，表明神经变性是由互补的功能丧失机制引起的。在人类和小鼠中，sTDP43转录本富含易感的运动神经元，并且我们观察到sTDP43在ALS患者的神经元和神经胶质中明显蓄积。总的来说，这些研究揭示了ALS中其他TDP43同工型的致病作用，并暗示sTDP43是这种疾病中运动神经元易感性的关键因素。