RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response.
RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response.
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DOI：
10.1038/s41467-017-02200-0
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发表时间：
2017-12-08
影响因子：
16.6
通讯作者：
Todd PK
中科院分区：
文献类型：
--
作者：
Green KM;Glineburg MR;Kearse MG;Flores BN;Linsalata AE;Fedak SJ;Goldstrohm AC;Barmada SJ;Todd PK
重复相关的非8月(RAN)翻译允许在致病的重复扩增处非常规地启动。由于RAN翻译在多种神经退行性疾病的发病机制中起作用，确定其机制基础可能会为治疗发展提供信息。在这里，我们分析了导致C9orf72相关的肌萎缩侧索硬化症和额颞部痴呆(C9RAN)的G4C2重复扩增的RAN翻译，以及导致脆性X相关震颤/共济失调综合征的CGG重复。我们发现c9RAN翻译是通过CAP和eIF4A依赖的机制启动的，该机制利用了CUG起始密码子。C9RAN和CGG RAN都被整合应激反应(ISR)激活选择性地增强。ISR增强的RAN翻译需要eIF2α磷酸化依赖的起始密码子保真度的改变。同时，CGG和G4C2重复触发磷酸化eIF2α依赖的应力颗粒形成和整体翻译抑制。这些发现支持一种模型，在该模型中，重复扩张会引发细胞应激条件，有利于有毒蛋白质的RAN翻译，从而创建一个潜在的前馈环路，从而导致神经退化。C9orf72的核苷酸重复扩增是神经退行性疾病的常见遗传原因。在这里，作者深入了解了该重复序列经历重复相关非AUG(RAN)翻译的分子机制，涉及整合的应激反应和eIF2α磷酸化。
Repeat-associated non-AUG (RAN) translation allows for unconventional initiation at disease-causing repeat expansions. As RAN translation contributes to pathogenesis in multiple neurodegenerative disorders, determining its mechanistic underpinnings may inform therapeutic development. Here we analyze RAN translation at G4C2 repeat expansions that cause C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9RAN) and at CGG repeats that cause fragile X-associated tremor/ataxia syndrome. We find that C9RAN translation initiates through a cap- and eIF4A-dependent mechanism that utilizes a CUG start codon. C9RAN and CGG RAN are both selectively enhanced by integrated stress response (ISR) activation. ISR-enhanced RAN translation requires an eIF2α phosphorylation-dependent alteration in start codon fidelity. In parallel, both CGG and G4C2 repeats trigger phosphorylated-eIF2α-dependent stress granule formation and global translational suppression. These findings support a model whereby repeat expansions elicit cellular stress conditions that favor RAN translation of toxic proteins, creating a potential feed-forward loop that contributes to neurodegeneration. A nucleotide repeat expansion in C9orf72 is a common genetic cause of neurodegenerative disorders. Here, the authors provide insight into the molecular mechanism by which this repeat undergoes Repeat-Associated Non-AUG (RAN) translation, implicating the integrated stress response and 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：
7.7
作者：
Andreev DE;O'Connor PB;Fahey C;Kenny EM;Terenin IM;Dmitriev SE;Cormican P;Morris DW;Shatsky IN;Baranov PV
通讯作者：
Baranov PV
影响因子：
4.8
作者：
Dmitriev, Sergey E.;Terenin, Ilya M.;Shatsky, Ivan N.
通讯作者：
Shatsky, Ivan N.
DOI：
10.1073/pnas.1509744112
发表时间：
2015-06-23
影响因子：
11.1
作者：
Barmada, Sami J.;Ju, Shulin;Finkbeiner, Steven
通讯作者：
Finkbeiner, Steven
影响因子：
2.7
作者：
Caschera, Filippo;Noireaux, Vincent
通讯作者：
Noireaux, Vincent