Nucleolar stress and impaired stress granule formation contribute to C9orf72 RAN translation-induced cytotoxicity
Nucleolar stress and impaired stress granule formation contribute to C9orf72 RAN translation-induced cytotoxicity
复制标题
核仁应激和应激颗粒形成受损导致 C9orf72 RAN 翻译诱导的细胞毒性
DOI：
10.1093/hmg/ddv005
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发表时间：
2015-05-01
影响因子：
3.5
通讯作者：
Ying, Zheng
中科院分区：
文献类型：
--
作者：
Tao, Zhouteng;Wang, Hongfeng;Ying, Zheng
肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）是两种常见的神经退行性疾病，它们与C9orf72非编码区的GGGGCC·GGCCCC重复RNA扩增有关。先前已有报道，GGGGCC·GGCCCC重复序列的非常规重复相关非ATG（RAN）翻译产生五种类型的二肽重复蛋白（称为RAN蛋白）：多聚甘氨酸 - 丙氨酸（GA）、多聚甘氨酸 - 脯氨酸（GP）、多聚甘氨酸 - 精氨酸（GR）、多聚脯氨酸 - 精氨酸（PR）和多聚脯氨酸 - 丙氨酸（PA）。尽管在患者中发现了RAN蛋白的聚集体，但RAN蛋白聚集是否诱导神经毒性尚不清楚。在本研究中，我们旨在了解所有五种RAN蛋白的生物学特性。令人惊讶的是，我们的结果表明，在我们的细胞模型中，这些RAN蛋白都不易聚集，并且这些RAN蛋白的周转不受泛素 - 蛋白酶体系统或自噬的影响。此外，多聚GR和多聚PR，而不是多聚GA、多聚GP或多聚PA，定位于核仁并诱导关键核仁成分核磷蛋白的易位，导致核仁应激和细胞死亡。这种多聚GR和多聚PR介导的核仁功能缺陷与核糖体RNA合成的抑制以及应激颗粒形成的受损有关。综上所述，本研究的结果提出了一个关于C9orf72相关ALS/FTD中RAN翻译介导的细胞毒性的分子机制的简单模型，其中核仁应激，而非蛋白质聚集，是C9orf72相关神经退行性变的主要促成因素。
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are the two common neurodegenerative diseases that have been associated with the GGGGCC center dot GGCCCC repeat RNA expansion in a noncoding region of C9orf72. It has been previously reported that unconventional repeat-associated non-ATG (RAN) translation of GGGGCC center dot GGCCCC repeats produces five types of dipeptide-repeat proteins (referred to as RAN proteins): poly-glycine-alanine (GA), poly-glycine-proline (GP), poly-glycine-arginine (GR), poly-proline-arginine (PR) and poly-proline-alanine (PA). Although protein aggregates of RAN proteins have been found in patients, it is unclear whether RAN protein aggregation induces neurotoxicity. In the present study, we aimed to understand the biological properties of all five types of RAN proteins. Surprisingly, our results showed that none of these RAN proteins was aggregate-prone in our cellular model and that the turnover of these RAN proteins was not affected by the ubiquitin-proteasome system or autophagy. Moreover, poly-GR and poly-PR, but not poly-GA, poly-GP or poly-PA, localized to the nucleolus and induced the translocation of the key nucleolar component nucleophosmin, leading to nucleolar stress and cell death. This poly-GR- and poly-PR-mediated defect in nucleolar function was associated with the suppression of ribosomal RNAsynthesis and the impairment of stress granule formation. Taken together, the results of the present study suggest a simple model of the molecular mechanisms underlying RAN translation-mediated cytotoxicity in C9orf72-linked ALS/FTD in which nucleolar stress, but not protein aggregation, is the primary contributor to C9orf72-linked neurodegeneration.