Pathogenic determinants and mechanisms of ALS/FTD linked to hexanucleotide repeat expansions in the C9orf72 gene.
Pathogenic determinants and mechanisms of ALS/FTD linked to hexanucleotide repeat expansions in the C9orf72 gene.
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DOI：
10.1016/j.neulet.2016.09.007
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发表时间：
2017-01-01
影响因子：
2.5
通讯作者：
Trotti D
中科院分区：
文献类型：
--
作者：
Wen X;Westergard T;Pasinelli P;Trotti D
肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）是两种明显不同的神经退行性疾病，前者的特征是大脑和脊髓中运动神经元的选择性丧失，后者的特征是额叶和颞叶的选择性萎缩。然而，多年来，越来越多的临床、病理和遗传学发现证据表明，ALS 和 FTD 属于同一临床病理谱系疾病。两种疾病最常见遗传原因的鉴定进一步支持了这一概念，即位于基因 C9orf72 非编码区的异常扩展的六核苷酸重复 GGGGCC 序列。人们提出了三种假设来解释这种重复扩展如何导致疾病：1）C9orf72单倍体不足扩展重复干扰基因的转录或翻译，导致C9orf72蛋白表达降低； 2）RNA功能获得——由扩增重复序列的有义和反义转录物形成的RNA焦点相互作用并隔离必需的RNA结合蛋白，引起神经毒性； 3) GGGGCC 重复序列扩展的重复相关非 ATG 启动 (RAN) 翻译 - 扩展的有义和反义重复序列的 RAN 翻译产生潜在的有毒二肽重复蛋白 (DPR)。在这篇综述中，我们评估了支持或反对 C9 ALS/FTD 疾病发病机制中每种拟议机制的当前证据。此外，还讨论了有争议的发现。最后，我们讨论了三种致病机制并不相互排斥并且所有三种机制都可能与疾病有关的可能性。
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two apparently distinct neurodegenerative diseases, the former characterized by selective loss of motor neurons in the brain and spinal cord and the latter characterized by selective atrophy of frontal and temporal lobes. Over the years, however, growing evidence from clinical, pathological and genetic findings has suggested that ALS and FTD belong to the same clinic-pathological spectrum disorder. This concept has been further supported by the identification of the most common genetic cause for both diseases, an aberrantly expanded hexanucleotide repeat GGGGCC sequence located in a non-coding region of the gene C9orf72. Three hypotheses have been proposed to explain how this repeats expansion causes diseases: 1) C9orf72 haploinsufficiency-expanded repeats interfere with transcription or translation of the gene, leading to decreased expression of C9orf72 protein; 2) RNA gain of function-RNA foci formed by sense and antisense transcripts of expanded repeats interact and sequester essential RNA binding proteins, causing neurotoxicity; 3) Repeat associated non-ATG initiated (RAN) translation of GGGGCC repeat expansion-RAN translation of expanded sense and antisense repeats produces potential toxic dipeptide repeat protein (DPR). In this review, we assess current evidence supporting or arguing against each proposed mechanism in C9 ALS/FTD disease pathogenesis. Additionally, controversial findings are also discussed. Lastly, we discuss the possibility that the three pathogenic mechanisms are not mutually exclusive and all three might be involved in disease.
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影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
通讯作者：
Petrucelli L
影响因子：
12.7
作者：
Cooper-Knock J;Higginbottom A;Stopford MJ;Highley JR;Ince PG;Wharton SB;Pickering-Brown S;Kirby J;Hautbergue GM;Shaw PJ
通讯作者：
Shaw PJ
影响因子：
14.5
作者：
Burrell, James R.;Kiernan, Matthew C.;Hodges, John R.
通讯作者：
Hodges, John R.
DOI：
10.1093/brain/awu120
发表时间：
2014-07
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Cooper-Knock J;Walsh MJ;Higginbottom A;Robin Highley J;Dickman MJ;Edbauer D;Ince PG;Wharton SB;Wilson SA;Kirby J;Hautbergue GM;Shaw PJ
通讯作者：
Shaw PJ
影响因子：
12.7
作者：
Al-Sarraj, Safa;King, Andrew;Shaw, Christopher E.
通讯作者：
Shaw, Christopher E.