Cryo-EM Analysis of Ribosomal Defects in C9ORF72-Associated Frontotemporal Dementia and ALS

摘要 额颞叶痴呆(FTD)是由额叶和/或前颞叶萎缩引起的 仅次于阿尔茨海默病的第二种最常见的痴呆症。FTD患者经常表现出 个性改变，失去同理心和去抑制能力，或语言障碍和运动 赤字。FTD最常见的遗传原因是GGGGCC(G4C2)重复扩增 C9ORF72基因的第一内含子。正义和反义重复RNA被翻译成5 在C9ORF72患者脑神经元中观察到的不同二肽重复(DPR)蛋白。 其中，聚(GR)和聚(PR)毒性最强，但具体是哪种尚不清楚 分子和结构的作用机制低于其神经毒性。在这个R21项目中，我们 将研究聚(GR)和聚(PR)生产的高分辨率结构机制 核糖体，潜在的顺式抑制翻译的扩大的G4C2重复和DPR 蛋白质，以及FTD患者神经元中直接的翻译失调。通过发现 C9ORF72引起FTD的分子机制及进一步开发高分辨工具 神经元的结构生物学，我们的项目可能会在神经科学研究和 痴呆症潜在的其他分子病理学的治疗进展。

Abstract Frontotemporal dementia (FTD), caused by atrophy of frontal and/or anterior temporal lobes, is the second most common form of dementia after Alzheimer’s disease. FTD patients often show changes in personality, loss of empathy and disinhibition, or language impairment and movement deficits. The most common genetic cause of FTD is a GGGGCC (G4C2) repeat expansion in the first intron of the C9ORF72 gene. The sense and antisense repeat RNAs are translated into 5 different dipeptide repeat (DPR) proteins that are observed in C9ORF72 patient brain neurons. Among them, poly(GR) and poly(PR) are most toxic but it remains largely unknown which specific molecular and structural mechanisms of action underly their neurotoxicity. In this R21 project, we will examine the high-resolution structural mechanisms of poly(GR) and poly(PR) production by the ribosome, the underlying cis-inhibition of translation by expanded G4C2 repeats and DPR proteins, and translation dysregulation directly in FTD patient neurons. By discovering the molecular mechanisms of C9ORF72-caused FTD and further developing tools for high-resolution structural biology in neurons, our project may open new directions in neuroscience research and therapeutics development of other molecular pathologies underlying dementia.