Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder. Mutations in C9orf72 and the resulting hexanucleotide repeat (GGGGCC) expansion (HRE) has been identified as a major cause of familial ALS, accounting for about 40 % of familial and 6 % of sporadic cases of ALS in Western patients. The pathological outcomes of HRE expansion in ALS have been recognized as the results of two mechanisms that include both the toxic gain-of-function and loss-of-function of C9ORF72. The gain of toxicity results from RNA and dipeptide repeats (DPRs). The HRE can be bidirectionally transcribed into RNA foci, which can bind to and disrupt RNA splicing, transport, and translation. The DPRs that include poly-glycine-alanine, poly-glycine-proline, poly-glycine- arginine, poly-proline-alanine, and poly-proline-arginine can induce toxicity by direct binding and sequestrating other proteins to interfere rRNA synthesis, ribosome biogenesis, translation, and nucleocytoplasmic transport. The C9ORF72 functions through binding to its partners-Smith-Magenis chromosome regions 8 (SMCR8) and WD repeat-containing protein (WDR41). Loss of C9ORF72 function results in impairment of autophagy, deregulation of autoimmunity, increased stress, and disruption of nucleocytoplasmic transport. Further insight into the mechanism in C9ORF72 HRE pathogenesis will facilitate identifying novel and effective therapeutic targets for ALS.

中文翻译：

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肌萎缩侧索硬化症 C9orf72 基因六核苷酸重复扩增的发病机制

肌萎缩侧索硬化症（ALS）是一种快速进展且致命的神经退行性疾病。突变在C9orf72由此产生的六核苷酸重复序列 (GGGGCC) 扩增 (HRE) 已被确定为家族性 ALS 的主要原因，约占西方患者中家族性 ALS 病例的 40% 和散发性 ALS 病例的 6%。ALS 中 HRE 扩增的病理结果已被认为是两种机制的结果，包括 C9ORF72 的毒性功能获得和功能丧失。RNA 和二肽重复序列 (DPR) 会增加毒性。HRE 可以双向转录成 RNA 焦点，RNA 焦点可以结合并破坏 RNA 剪接、运输和翻译。包括聚甘氨酸-丙氨酸、聚甘氨酸-脯氨酸、聚甘氨酸-精氨酸、聚脯氨酸-丙氨酸和聚脯氨酸-精氨酸的DPR可以通过直接结合和隔离其他蛋白质来干扰rRNA合成、核糖体而诱导毒性。生物发生、翻译和核细胞质运输。C9ORF72 通过与其伙伴——Smith-Magenis 染色体区域 8 (SMCR8) 和含有 WD 重复序列的蛋白 (WDR41) 结合而发挥作用。C9ORF72 功能丧失会导致自噬受损、自身免疫失调、应激增加以及核细胞质运输破坏。进一步深入了解 C9ORF72 HRE 发病机制将有助于确定 ALS 的新型有效治疗靶点。