Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis.
Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis.
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DOI：
10.1038/s41591-018-0071-1
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发表时间：
2018-08
期刊：
影响因子：
82.9
通讯作者：
Petrucelli L
中科院分区：
文献类型：
--
作者：
Zhang YJ;Gendron TF;Ebbert MTW;O'Raw AD;Yue M;Jansen-West K;Zhang X;Prudencio M;Chew J;Cook CN;Daughrity LM;Tong J;Song Y;Pickles SR;Castanedes-Casey M;Kurti A;Rademakers R;Oskarsson B;Dickson DW;Hu W;Gitler AD;Fryer JD;Petrucelli L
额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS）的主要遗传原因是C9orf72 G4C2重复扩增。被提出的扩增导致c9FTD/ALS的机制包括含有重复序列的RNA和从这些转录物翻译的二肽重复序列蛋白的毒性。为了研究poly（GR）二肽重复蛋白在哺乳动物体内模型c9FTD/ALS发病机制中的作用，我们在脑内培养了表达GFP-(GR)100的小鼠。GFP-(GR)100小鼠通过弥漫性细胞质poly（GR）的积累出现年龄依赖性神经变性、脑萎缩、运动和记忆缺陷。在GFP-(GR)100小鼠中，Poly（GR）与核糖体亚基和翻译起始因子eIF3η共定位，重要的是在c9FTD/ALS患者中。结合GFP-(GR)100小鼠核糖体相关基因的差异表达，这些发现证明了多（GR）介导的核糖体窘迫。事实上，poly（GR）抑制了HEK293T细胞中典型和非典型蛋白的翻译，也诱导了应激颗粒的形成并延迟了它们的分解。这些数据表明，聚（GR）通过损害蛋白质翻译和应激颗粒动力学来促进c9FTD/ALS，从而导致慢性细胞应激并阻止细胞产生有效的应激反应。因此，减少多聚（GR）和/或中断多聚（GR）与核糖体和应激颗粒相关蛋白之间的相互作用可能是恢复体内平衡的潜在治疗策略。
The major genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a C9orf72 G4C2 repeat expansion. Proposed mechanisms by which the expansion causes c9FTD/ALS include toxicity from repeat-containing RNA and from dipeptide repeat proteins translated from these transcripts. To investigate the contribution of poly(GR) dipeptide repeat proteins to c9FTD/ALS pathogenesis in a mammalian in vivo model, we generated mice that expressed GFP-(GR)100 in the brain. GFP-(GR)100 mice developed age-dependent neurodegeneration, brain atrophy, and motor and memory deficits through the accumulation of diffuse, cytoplasmic poly(GR). Poly(GR) co-localized with ribosomal subunits and the translation initiation factor eIF3η in GFP-(GR)100 mice and, of importance, in c9FTD/ALS patients. Combined with the differential expression of ribosome-associated genes in GFP-(GR)100 mice, these findings demonstrate poly(GR)-mediated ribosomal distress. Indeed, poly(GR) inhibited canonical and non-canonical protein translation in HEK293T cells, and also induced the formation of stress granules and delayed their disassembly. These data suggest that poly(GR) contributes to c9FTD/ALS by impairing protein translation and stress granule dynamics, consequently causing chronic cellular stress and preventing cells from mounting an effective stress response. Decreasing poly(GR) and/or interrupting interactions between poly(GR) and ribosomal and stress granule-associated proteins may thus represent potential therapeutic strategies to restore homeostasis.
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DOI：
10.1093/biostatistics/kxr054
发表时间：
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期刊：
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影响因子：
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DOI：
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发表时间：
2014-09-05
期刊：
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发表时间：
2014-07
期刊：
Brain : a journal of neurology
影响因子：
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作者：
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