Abstract：
TAR binding protein 43 (TDP-43) is normally present in the nucleus but mislocalized in the cytoplasm in a number of neurodegenerative diseases including Huntington\'s disease (HD). The nuclear loss of TDP-43 impairs gene transcription and regulation. However, it remains to be investigated whether loss of TDP-43 influences trinucleotide CAG repeat expansion in the HD gene, a genetic cause for HD. Here we report that CRISPR/Cas9 mediated-knock down of endogenous TDP-43 in the striatum of HD knock-in mice promoted CAG repeat expansion, accompanied by the increased expression of the DNA mismatch repair genes, Msh3 and Mlh1, which have been reported to increase trinucleotide repeat instability. Furthermore, suppressing Msh3 and Mlh1 by CRISPR/Cas9 targeting diminished the CAG repeat expansion. These findings suggest that nuclear TDP-43 deficiency may dysregulate the expression of DNA mismatch repair genes, leading to CAG repeat expansion and contributing to the pathogenesis of CAG repeat diseases.
摘要：
TAR结合蛋白43（TDP-43）通常存在于细胞核中，但在许多神经退行性疾病（包括亨廷顿氏病（HD））中在细胞质中定位错误。TDP-43的核丢失损害基因转录和调节。然而,TDP-43的缺失是否影响HD基因中的三核苷酸CAG重复扩增还有待研究，HD的遗传原因。在这里，我们报道了CRISPR/Cas9介导的HD敲入小鼠纹状体中内源性TDP-43的敲低促进了CAG重复扩增，伴随着DNA错配修复基因的表达增加，已报道Msh3和Mlh1增加三核苷酸重复不稳定性。此外，通过CRISPR/Cas9靶向抑制Msh3和Mlh1减少了CAG重复扩增。这些发现表明，核TDP-43缺陷可能会失调DNA错配修复基因的表达，导致CAG重复扩展，并有助于CAG重复疾病的发病机制。数据可用性：文章和补充信息中提供了支持本研究结果的关键数据。本文报道的RNA测序可以在https://doi.org/10.6084/m9找到。图22639429。
