C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia: gain or loss of function?
C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia: gain or loss of function?
复制标题
C9ORF72肌萎缩性侧索硬化和额颞痴呆：功能的增益或丧失？
DOI：
10.1097/wco.0000000000000130
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发表时间：
2014-10
影响因子：
4.8
通讯作者：
Isaacs AM
中科院分区：
文献类型：
--
作者：
Mizielinska S;Isaacs AM
与9号染色体开放阅读框架72(C9orf72)相关的肌萎缩侧索硬化症和额颞叶痴呆的分子机制正在迅速出现。已经假设了两种潜在的疾病机制--功能增强或丧失。我们提供了支持或反对功能获得和功能丧失机制的最新进展的概述。自从2011年发现C9orf72的非编码重复扩增导致9号染色体连锁的肌萎缩侧索硬化症和额颞部痴呆以来，大量研究对该疾病的临床、病理和发病机制进行了研究。患者大脑和功能工作中C9orf72水平的降低支持了功能丧失，揭示了C9orf72蛋白在内吞和自噬途径以及运动功能中的作用。患者大脑中存在重复的RNA和蛋白质聚集体，这支持了功能的获得。被称为RNA焦点的重复RNA聚合体是非编码重复扩张性疾病的标志，已被证明隔离参与RNA剪接、编辑、核输出和核仁功能的蛋白质。重复相关的非ATG依赖的翻译会产生有毒的二肽重复蛋白，在患者组织中形成包涵体。针对C9orf72的反义寡核苷酸已显示出对抗功能获得毒性的前景。在了解肌萎缩侧索硬化症和额颞叶痴呆的这种常见遗传原因方面正在迅速取得进展。总体而言，目前数据的权重有利于获得作为最重要疾病机制的功能，这对开发有效和有针对性的治疗方法具有重要意义。
The molecular mechanisms that underlie chromosome 9 open reading frame 72 (C9orf72)-associated amyotrophic lateral sclerosis and frontotemporal dementia are rapidly emerging. Two potential disease mechanisms have been postulated – gain or loss of function. We provide an overview of recent advances that support or oppose gain-of-function and loss-of-function mechanisms. Since the discovery that a noncoding repeat expansion in C9orf72 was responsible for chromosome 9-linked amyotrophic lateral sclerosis and frontotemporal dementia in 2011, a plethora of studies have investigated clinical, pathological and mechanistic aspects of the disease. Loss of function is supported by reduced levels of C9orf72 in patient brain and functional work, revealing a role of the C9orf72 protein in endocytic and autophagic pathways and motor function. Gain of function is supported by the presence in patient brain of both repeat RNA and protein aggregates. Repeat RNA aggregates termed RNA foci, a hallmark of noncoding repeat expansion diseases, have been shown to sequester proteins involved in RNA splicing, editing, nuclear export and nucleolar function. Repeat-associated non-ATG dependent translation gives rise to toxic dipeptide repeat proteins that form inclusions in patient tissue. Antisense oligonucleotides targeting C9orf72 have shown promise for combating gain-of-function toxicity. Rapid progress is being made towards understanding this common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Overall, the weight of data currently sits in favour of gain of function as the most important disease mechanism, which has important implications for the development of effective and targeted therapies.