Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN, USA.
Nat Med. 2018 Aug;24(8):1136-1142. doi: 10.1038/s41591-018-0071-1. Epub 2018 Jun 25.
The major genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a C9orf72 GC 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) in the brain. GFP-(GR) 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) mice and, of importance, in c9FTD/ALS patients. Combined with the differential expression of ribosome-associated genes in GFP-(GR) 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.
C9orf72 基因 GC 重复扩增是额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS）的主要遗传病因。该重复扩增导致 c9FTD/ALS 的机制包括重复 RNA 毒性和从这些转录本翻译而来的二肽重复蛋白毒性。为了在哺乳动物体内模型中研究聚（GR）二肽重复蛋白对 c9FTD/ALS 发病机制的贡献，我们生成了在大脑中表达 GFP-（GR）的小鼠。GFP-（GR）小鼠通过弥漫性细胞质聚（GR）的积累，表现出年龄依赖性神经退行性变、脑萎缩以及运动和记忆缺陷。聚（GR）与核糖体亚基和翻译起始因子 eIF3η 在 GFP-（GR）小鼠中共同定位，这一点非常重要，在 c9FTD/ALS 患者中也存在共定位。结合 GFP-（GR）小鼠中核糖体相关基因的差异表达，这些发现表明聚（GR）介导的核糖体应激。事实上，聚（GR）抑制了 HEK293T 细胞中的经典和非经典蛋白翻译，并且还诱导了应激颗粒的形成并延迟了其解体。这些数据表明，聚（GR）通过损害蛋白翻译和应激颗粒动力学而导致慢性细胞应激，从而阻止细胞做出有效的应激反应，从而导致 c9FTD/ALS。因此，减少聚（GR）和/或中断聚（GR）与核糖体和应激颗粒相关蛋白之间的相互作用，可能代表恢复体内平衡的潜在治疗策略。
