Rationale: A C9orf72 hexanucleotide repeat expansion (GGGGCC) is the most common genetic origin of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Haploinsufficiency of C9orf72 has been proposed as a possible disease mechanism (loss-of-function mechanism). Additionally, the aberrantly activated unfolded protein response (UPR) and stress granule (SG) formation are associated with the etiopathology of both ALS and FTD. However, the molecular determinants in this pathogenesis are not well characterized./nMethods: We performed an immunoprecipitation-mass spectrometry (IP-MS) assay to identify potential proteins interacting with the human C9orf72 protein. We used C9orf72 knockout cell and rat models to determine the roles of C9orf72 in translation initiation and the stress response./nResults: Here, we show that C9orf72, which is genetically and pathologically related to ALS and FTD, interacts with eukaryotic initiation factor 2 subunit alpha (eIF2α) and regulates its function in translation initiation. C9orf72 knockout weakens the interaction between eIF2α and eIF2B5, leading to global translation inhibition. Moreover, the loss of C9orf72 results in primary ER stress with activated UPR in rat spleens, which is one of the causes of splenomegaly with inflammation in C9orf72^-/- rats. Finally, C9orf72 delays SG formation by interacting with eIF2α in stressed cells./nConclusions: In summary, these data reveal that C9orf72 modulates translation initiation, the UPR and SG formation, which have implications for understanding ALS/FTD pathogenesis.

中文翻译：

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C9orf72 通过与 eIF2α 相互作用调节未折叠蛋白反应和应激颗粒形成

基本原理： C9orf72六核苷酸重复扩增 (GGGGCC) 是肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 最常见的遗传起源。C9orf72 的单倍剂量不足已被提议作为一种可能的疾病机制（功能丧失机制）。此外，异常激活的未折叠蛋白反应 (UPR) 和应激颗粒 (SG) 形成与 ALS 和 FTD 的病因病理学相关。然而，这种发病机制中的分子决定因素并未得到很好的表征。/n方法：我们进行了免疫沉淀-质谱 (IP-MS) 测定，以确定与人 C9orf72 蛋白相互作用的潜在蛋白质。我们使用了 C9orf72敲除细胞和大鼠模型以确定 C9orf72 在翻译起始和应激反应中的作用。/n结果：在这里，我们显示 C9orf72 在遗传和病理学上与 ALS 和 FTD 相关，与真核起始因子 2 亚基 alpha 相互作用（ eIF2α) 并调节其在翻译起始中的功能。C9orf72敲除削弱了 eIF2α 和 eIF2B5 之间的相互作用，导致全局翻译抑制。此外，C9orf72 的缺失导致大鼠脾脏中原发性内质网应激和 UPR 激活，这是C9orf72 ^-/-大鼠脾肿大伴炎症的原因之一。最后，C9orf72 通过与应激细胞中的 eIF2α 相互作用来延迟 SG 的形成。/n结论：总之，这些数据表明 C9orf72 调节翻译起始、UPR 和 SG 形成，这对理解 ALS/FTD 发病机制具有重要意义。