重复出现的问题：C9orf72 衍生二肽重复蛋白的组合效应。

Repeated repeat problems: Combinatorial effect of C9orf72-derived dipeptide repeat proteins.

机构信息

Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33612, USA.

出版信息

Int J Biol Macromol. 2019 Apr 15;127:136-145. doi: 10.1016/j.ijbiomac.2019.01.035. Epub 2019 Jan 9.

DOI:10.1016/j.ijbiomac.2019.01.035

PMID:30639592

Abstract

A microsatellite expansion mutation in C9orf72 is the most common genetic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). The expansion mutation leads to C9orf72 loss of function, RNA foci formation, and generation of five species of non-AUG RAN translated dipeptide repeat proteins (DPRs), such as poly(GA), poly(GP), poly(GR), poly(PA), and poly(PR). Although one cell can contain more than type of DPRs, information about interplay between different DPR species is limited. Here we show that the combined expression of distinct C9orf72-derived dipeptide repeat species produces cellular outcomes and structural differences that are unique compared to the expression of a single DPR species, suggesting the complex biological interactions that occur when multiple DPR variants are simultaneously expressed. Our data highlights the need for further analysis of how combined expression of different DPRs affects the disease state.

摘要

C9orf72 中的微卫星扩展突变是肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 的最常见遗传原因。该扩展突变导致 C9orf72 失去功能、RNA 焦点形成，并产生五种非 AUG RAN 翻译的二肽重复蛋白 (DPR)，如聚 (GA)、聚 (GP)、聚 (GR)、聚 (PA) 和聚 (PR)。尽管一个细胞可以包含多种 DPR，但关于不同 DPR 物种之间相互作用的信息有限。在这里，我们表明，不同 C9orf72 衍生二肽重复物种的组合表达产生了与单一 DPR 物种表达相比独特的细胞结果和结构差异，这表明当多种 DPR 变体同时表达时会发生复杂的生物学相互作用。我们的数据强调了需要进一步分析不同 DPR 的组合表达如何影响疾病状态。