在C9orf72基因非编码区异常扩增的核苷酸重复序列是ALS/FTLD最常见的遗传原因。多项研究，包括我们的，均提示由非经典蛋白翻译途径得到的富含精氨酸的重复二肽(R-rich DPRs)引发神经元死亡。文献提示TDP-43蛋白聚集物是ALS/FTLD经典的病理特征，且TDP-43聚集物出现在DPRs显著积累之后并与神经变性表型相关。我们前期研究发现R-rich DPRs引起TDP-43聚集体形成以及DNA损伤、核膜损害等。综上，我们提出假设R-rich DPRs破坏TDP-43核转运，形成TDP-43聚集体，引起神经毒性。因此，设计本项目：拟系统明确R-rich DPRs与TDP-43聚集物形成的关系；探索内在的分子机制；筛选调节细胞核运输的小分子化合物，寻找潜在干预靶点。

Expanded GGGGCC repeats in the non-coding region of C9orf72 gene is the most common genetic cause of ALS/FTLD. Multiple studies, including our own, suggested arginine-rich (R-rich) dipeptide repeat proteins (DPRs), poly-GlyArg (poly-GR) and poly-ProArg (poly-PR), produced by unconventional translation of these expanded repeats cause in vitro and in vivo neuronal death. Mislocalization of the nuclear protein TDP-43 to cytoplasmic aggregates is the pathological hallmark of ALS/FTLD. In addition, TDP-43 pathology is suggested to be preceded by DPRs accumulation and is likely to associate with neurodegeneration in C9orf72 mutation linked ALS/FTLD (C9-ALS/FTLD), highlighting the significance of TDP-43 pathology. Our preliminary results suggested that expression of R-rich DPRs led to formation of TDP-43 cytoplasmic aggregates,DNA damage and nuclear envelope abnormality. Interestingly, several recent studies have shown that nuclear transport proteins are prominent genetic modifiers of R-rich DPRs neurotoxicity. Hence, this proposal will comprehensively investigate how TDP-43 contributes to neurotoxicity caused by R-rich DPRs in C9-ALS/FTLD, focusing on its nucleocytoplasmic transport. We will thoroughly characterize the association between R-rich DPRs and TDP-43 aggregates, how TDP-43 might be affected and what are the consequences. We will determine whether nuclear partitioning of the R-rich DPRs is required for neurotoxicity. Finally, we will determine whether modulation of nucleocytoplasmic transport through chemical compounds might be therapeutic for ALS/FTLD, providing potential therapeutic targets.