Cytoplasmic inclusions and loss of nuclear TDP-43 are key pathological features found in several neurodegenerative disorders, suggesting both gain- and loss-of-function mechanisms of disease. To study gain-of-function, TDP-43 overexpression has been used to generate in vitro and in vivo model systems. We analyzed RNA-seq datasets from mouse and human neurons overexpressing TDP-43 to explore species specific splicing patterns. We explored the dynamics between TDP-43 levels and exon repression in vitro. Furthermore we analyzed human brain samples and publicly available RNA datasets to explore the relationship between exon repression and disease. Our study shows that excessive levels of nuclear TDP-43 protein lead to constitutive exon skipping that is largely species-specific. Furthermore, while aberrant exon skipping is detected in some human brains, it is not correlated with disease, unlike the incorporation of cryptic exons that occurs after loss of TDP-43. Our findings emphasize the need for caution in interpreting TDP-43 overexpression data and stress the importance of controlling for exon skipping when generating models of TDP-43 proteinopathy.

中文翻译：

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核 TDP-43 升高诱导组成型外显子跳跃


细胞质内含物和核 TDP-43 缺失是多种神经退行性疾病中发现的关键病理特征，表明疾病的功能获得和功能丧失机制。为了研究功能获得，TDP-43 过表达已被用来生成体外和体内模型系统。我们分析了过表达 TDP-43 的小鼠和人类神经元的 RNA-seq 数据集，以探索物种特异性剪接模式。我们在体外探索了 TDP-43 水平和外显子抑制之间的动态。此外，我们分析了人脑样本和公开的 RNA 数据集，以探索外显子抑制与疾病之间的关系。我们的研究表明，核 TDP-43 蛋白水平过高会导致组成型外显子跳跃，这在很大程度上是物种特异性的。此外，虽然在一些人脑中检测到异常的外显子跳跃，但它与疾病无关，这与 TDP-43 丢失后发生的神秘外显子的掺入不同。我们的研究结果强调在解释 TDP-43 过表达数据时需要谨慎，并强调在生成 TDP-43 蛋白病模型时控制外显子跳跃的重要性。