GGGGCC六核苷酸重复序列介导的非AUG启动子依赖翻译产物毒性双肽蛋白是C9orf72基因突变的主要致病机制之一。我们在前期工作中通过人类全基因组CRISPR-Cas9敲除慢病毒文库筛选获得了能特异性调节G4C2 RAN翻译产物水平的内源性调节基因，其中UPF1及SMG6均为无义介导的mRNA降解信号通路相关基因。随后我们在双荧光素酶C9orf72 mini-gene剪接报告载体细胞中进一步验证了UPF1敲除会上调G4C2 RAN翻译产物聚甘氨酸-丙氨酸。在本课题中，我们将研究UPF1对C9orf72 G4C2 RAN翻译产物的调节作用及其分子机制，以及以NMD信号通路为靶点减缓神经元死亡的可能性。本课题将首次在细胞及分子水平上发现NMD信号通路对G4C2 RAN翻译产物的调节作用及分子机制，为临床上治疗核苷酸重复扩增突变的神经退行性疾病提供新的思路。

The aberrant accumulation of the dipeptide repeat (DPR) proteins produced by GGGGCC repeat associated non-AUG(RAN) translation is the main pathogenic mechanism of the hexanucleotide G4C2 expansion in C9orf72 gene. We performed the human genome-wide CRISPR-Cas9 screens for endogenous modifiers of DPR production. We identified two genes, UPF1 and SMG6, of which both are the nonsense mediated decay factors. We further confirmed the effect of UPF1 on the production of poly GA(poly Glycine-Alanine) with our dual-luciferase mini-gene splicing reporter cell. In this study, we will investigate the effect of UPF1 on the DPR production from G4C2 expansion and the underlying mechanism behind this effect. This study will for the first time address the potential effect and the underlying mechanism of UPF1 regulating the DPR production from G4C2 repeats, and it may provide a novel therapeutic target to treat the inherit neurodegenerative disease with nucleotide repeat expansion.