The C9orf72 repeat expansion causes amyotrophic lateral sclerosis and frontotemporal dementia, but the poor correlation between C9orf72-specific pathology and TDP-43 pathology linked to neurodegeneration hinders targeted therapeutic development. Here, we addressed the role of the aggregating dipeptide repeat proteins resulting from unconventional translation of the repeat in all reading frames. Poly-GA promoted cytoplasmic mislocalization and aggregation of TDP-43 non-cell-autonomously, and anti-GA antibodies ameliorated TDP-43 mislocalization in both donor and receiver cells. Cell-to-cell transmission of poly-GA inhibited proteasome function in neighboring cells. Importantly, proteasome inhibition led to the accumulation of TDP-43 ubiquitinated within the nuclear localization signal (NLS) at lysine 95. Mutagenesis of this ubiquitination site completely blocked poly-GA-dependent mislocalization of TDP-43. Boosting proteasome function with rolipram reduced both poly-GA and TDP-43 aggregation. Our data from cell lines, primary neurons, transgenic mice, and patient tissue suggest that poly-GA promotes TDP-43 aggregation by inhibiting the proteasome cell-autonomously and non-cell-autonomously, which can be prevented by inhibiting poly-GA transmission with antibodies or boosting proteasome activity with rolipram.

中文翻译：

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C9orf72 poly-（Gly-Ala）的细胞间传输触发了ALS / FTD的关键功能。

C9orf72重复扩增导致肌萎缩性侧索硬化和额颞痴呆，但与神经变性相关的C9orf72特异性病理学和TDP-43病理学之间的相关性较弱，阻碍了靶向治疗的发展。在这里，我们解决了由于所有阅读框中重复出现的非常规翻译而导致的聚集二肽重复蛋白的作用。Poly-GA可以非细胞自主地促进TDP-43的胞质错位和聚集，而抗GA抗体可以改善供体和受体细胞中TDP-43的错位。聚GA的细胞间传递抑制了邻近细胞中的蛋白酶体功能。重要的是，蛋白酶体的抑制导致在赖氨酸95处的核定位信号（NLS）中泛素化的TDP-43的积累。该泛素化位点的诱变完全阻断了TDP-43的聚GA依赖性错位。用咯利普兰增强蛋白酶体功能可减少聚GA和TDP-43的聚集。我们从细胞系，原代神经元，转基因小鼠和患者组织获得的数据表明，poly-GA通过自主地和非自主地抑制蛋白酶体来促进TDP-43聚集，而这可以通过抑制poly-GA的传播来预防。或与咯利普兰增强蛋白酶体活性。