C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation.
C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation.
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DOI：
10.1038/s41467-017-02495-z
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发表时间：
2018-01-04
影响因子：
16.6
通讯作者：
Sun S
中科院分区：
文献类型：
--
作者：
Cheng W;Wang S;Mestre AA;Fu C;Makarem A;Xian F;Hayes LR;Lopez-Gonzalez R;Drenner K;Jiang J;Cleveland DW;Sun S
C9ORF72中六核苷酸重复序列的扩张是肌萎缩侧索硬化症(ALS)和额颞痴呆(FTD)的最常见原因。在这里，我们证明了(GGGGCC)n-RNA在没有5‘-帽的情况下，在体内可以开始重复相关的非AUG(RAN)翻译成多肽。C9ORF72正义重复序列的RAN翻译的主要RNA底物被证明是拼接的第一个内含子，在它从最初的前mRNA中被切除并运输到细胞质中之后。不依赖帽的RAN翻译被证明是通过真核细胞起始因子-2的α亚单位(eIF2α)的磷酸化而被不同的应激刺激上调的，eIF2是整合应激反应的核心事件。抑制磷酸化eIF2α信号通路的化合物被证明抑制RAN翻译。由于多二肽本身可以诱导应激，这些发现支持一个前馈循环，其初始重复介导的毒性增强RAN翻译和随后通过ISR产生额外的多二肽，从而促进疾病的进展。六核苷酸GGGGCC重复序列在C9ORF72中的扩展是肌萎缩侧索硬化症(ALS)和额颞痴呆(FTD)的最常见原因。在这里，作者证明了(GGGGCC)n翻译可以在没有5‘-帽的情况下开始，并且这种帽非依赖性的翻译在胁迫下通过eIF2α的磷酸化而上调。
Hexanucleotide repeat expansion in C9ORF72 is the most frequent cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we demonstrate that the repeat-associated non-AUG (RAN) translation of (GGGGCC)n-containing RNAs into poly-dipeptides can initiate in vivo without a 5′-cap. The primary RNA substrate for RAN translation of C9ORF72 sense repeats is shown to be the spliced first intron, following its excision from the initial pre-mRNA and transport to the cytoplasm. Cap-independent RAN translation is shown to be upregulated by various stress stimuli through phosphorylation of the α subunit of eukaryotic initiation factor-2 (eIF2α), the core event of an integrated stress response (ISR). Compounds inhibiting phospho-eIF2α-signaling pathways are shown to suppress RAN translation. Since the poly-dipeptides can themselves induce stress, these findings support a feedforward loop with initial repeat-mediated toxicity enhancing RAN translation and subsequent production of additional poly-dipeptides through ISR, thereby promoting progressive disease. Hexanucleotide GGGGCC repeat expansion in C9ORF72 is the most frequent cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here the authors show that (GGGGCC)n translation can initiate without a 5′-cap, and this cap-independent translation is upregulated by stress mediated through eIF2α phosphorylation.
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影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
通讯作者：
Petrucelli L
影响因子：
30.8
作者：
Kim, Hyung-Jun;Raphael, Alya R.;LaDow, Eva S.;McGurk, Leeanne;Weber, Ross A.;Trojanowski, John Q.;Lee, Virginia M-Y;Finkbeiner, Steven;Gitler, Aaron D.;Bonini, Nancy M.
通讯作者：
Bonini, Nancy M.
DOI：
10.1038/nrn.2016.38
发表时间：
2016-06
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Haeusler AR;Donnelly CJ;Rothstein JD
通讯作者：
Rothstein JD
影响因子：
16.2
作者：
DeJesus-Hernandez M;Mackenzie IR;Boeve BF;Boxer AL;Baker M;Rutherford NJ;Nicholson AM;Finch NA;Flynn H;Adamson J;Kouri N;Wojtas A;Sengdy P;Hsiung GY;Karydas A;Seeley WW;Josephs KA;Coppola G;Geschwind DH;Wszolek ZK;Feldman H;Knopman DS;Petersen RC;Miller BL;Dickson DW;Boylan KB;Graff-Radford NR;Rademakers R
通讯作者：
Rademakers R
影响因子：
16.2
作者：
Bañez-Coronel M;Ayhan F;Tarabochia AD;Zu T;Perez BA;Tusi SK;Pletnikova O;Borchelt DR;Ross CA;Margolis RL;Yachnis AT;Troncoso JC;Ranum LP
通讯作者：
Ranum LP