Poly-dipeptides encoded by the C9ORF72 repeats block global protein translation
Poly-dipeptides encoded by the C9ORF72 repeats block global protein translation
复制标题
DOI：
10.1093/hmg/ddw052
复制
发表时间：
2016-05-01
影响因子：
3.5
通讯作者：
Urano, Fumihiko
中科院分区：
文献类型：
--
作者：
Kanekura, Kohsuke;Yagi, Takuya;Urano, Fumihiko
染色体9开放阅读框72（C9 orf 72）基因非编码区中GGGGCC六核苷酸重复序列的扩增是额颞叶痴呆（FTD）和肌萎缩侧索硬化（ALS）最常见的遗传原因。这种遗传改变导致从GGGGCC六核苷酸重复翻译的五种类型的聚二肽的积累。其中，聚-脯氨酸-精氨酸（poly-PR）和聚-甘氨酸-精氨酸（poly-GR）肽已知是神经毒性的。然而，与这些聚二肽相关的神经毒性机制尚不清楚。蛋白质组学方法鉴定了许多与聚PR肽相互作用的蛋白质，包括mRNA结合蛋白、核糖体蛋白、翻译起始因子和翻译延伸因子。来自C9 orf 72 ALS患者的脑切片的免疫染色显示，聚GR与mRNA结合蛋白hnRNPA 1共定位。体外翻译实验表明，聚PR和聚GR肽与mRNA形成不溶性复合物，抑制翻译因子进入mRNA，阻断蛋白质翻译。我们的研究结果表明，受损的蛋白质翻译介导的聚PR和聚GR肽在神经毒性中发挥作用，并揭示了改变的途径的聚二肽-mRNA复合物是潜在的治疗C9 orf 72 FTD/ALS的治疗目标。
The expansion of the GGGGCC hexanucleotide repeat in the non-coding region of the Chromosome 9 open-reading frame 72 (C9orf72) gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This genetic alteration leads to the accumulation of five types of poly-dipeptides translated from the GGGGCC hexanucleotide repeat. Among these, poly-proline-arginine (poly-PR) and poly-glycine-arginine (poly-GR) peptides are known to be neurotoxic. However, the mechanisms of neurotoxicity associated with these poly-dipeptides are not clear. A proteomics approach identified a number of interacting proteins with poly-PR peptide, including mRNA-binding proteins, ribosomal proteins, translation initiation factors and translation elongation factors. Immunostaining of brain sections from patients with C9orf72 ALS showed that poly-GR was colocalized with a mRNA-binding protein, hnRNPA1. In vitro translation assays showed that poly-PR and poly-GR peptides made insoluble complexes with mRNA, restrained the access of translation factors to mRNA, and blocked protein translation. Our results demonstrate that impaired protein translation mediated by poly-PR and poly-GR peptides plays a role in neurotoxicity and reveal that the pathways altered by the poly-dipeptides-mRNA complexes are potential therapeutic targets for treatment of C9orf72 FTD/ALS.