BACKGROUND TAR DNA-binding protein 43 (TDP-43) is a nuclear protein, but it is redistributed in the neuronal cytoplasm in both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Because small transgenic animal models often lack cytoplasmic TDP-43, how the cytoplasmic accumulation of TDP-43 contributes to these diseases remains unclear. The current study is aimed at studying the mechanism of cytoplasmic pathology of TDP-43. RESULTS We established transgenic pigs expressing mutant TDP-43 (M337V). This pig model shows severe phenotypes and early death. We found that transgenic TDP-43 is also distributed in the cytoplasm of neuronal cells in the spinal cord and brain. Transgenic TDP-43 interacts with PSF, an RNA splicing factor that associates with NeuN to regulate neuronal RNA splicing. The interaction of TDP-43, PSF and NeuN causes PSF and NeuN mislocalize into the neuronal cytoplasm in transgenic pigs. Consistently, abnormal PSF-related neuronal RNA splicing is seen in TDP-43 transgenic pigs. The cytoplasmic localization of PSF and NeuN as well as abnormal PSF-related neuronal RNA splicing was also found in ALS patient brains. CONCLUSION Our findings from a large mammalian model suggest that cytoplasmic mutant TDP-43 could reduce the nuclear function of RNA splicing factors, contributing to neuropathology.

中文翻译：

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TDP-43转基因猪脑中RNA剪接因子的胞质错定位和异常神经元基因剪接。

背景技术TAR DNA结合蛋白43（TDP-43）是一种核蛋白，但在肌萎缩性侧索硬化症（ALS）和额颞叶变性（FTLD）中都重新分布在神经元细胞质中。由于小型转基因动物模型通常缺乏细胞质TDP-43，因此尚不清楚TDP-43的细胞质积累如何导致这些疾病。当前的研究旨在研究TDP-43的细胞质病理机制。结果我们建立了表达突变型TDP-43（M337V）的转基因猪。该猪模型显示出严重的表型和早期死亡。我们发现转基因TDP-43也分布在脊髓和大脑中神经元细胞的细胞质中。转基因TDP-43与PSF相互作用，PSF是一种RNA剪接因子，与NeuN相关联以调节神经元RNA剪接。TDP-43的相互作用 PSF和NeuN导致PSF和NeuN在转基因猪中误定位到神经元细胞质中。一致地，在TDP-43转基因猪中发现了异常的PSF相关神经元RNA剪接。在ALS患者的大脑中也发现了PSF和NeuN的胞质定位以及与PSF相关的异常神经元RNA剪接。结论我们从大型哺乳动物模型中获得的发现表明，胞质突变体TDP-43可能降低RNA剪接因子的核功能，从而有助于神经病理学。