There has been an awakening: Emerging mechanisms of C9orf72 mutations in FTD/ALS.
There has been an awakening: Emerging mechanisms of C9orf72 mutations in FTD/ALS.
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DOI：
10.1016/j.brainres.2016.04.004
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发表时间：
2016-09-15
期刊：
影响因子：
2.9
通讯作者：
Tsuiji, Hitomi
中科院分区：
文献类型：
--
作者：
Gitler, Aaron D.;Tsuiji, Hitomi
C9orf72突变是肌萎缩侧索硬化症（ALS）和额颞叶痴呆症（FTD）最常见的遗传原因，这一发现唤醒了人们对破译这一神秘基因突变如何导致疾病以及如何阻止疾病的兴趣。C9orf72在基因的非编码区含有一个六核苷酸重复序列GGGGCC，该重复序列的大量扩增导致ALS，FTD，或两者（FTD/ALS）。许多问题摆在面前。这个基因通常做什么？GGGGCC重复序列的大量扩增对该基因的功能有什么影响？六核苷酸重复扩增是否具有与C9orf72功能无关的额外病理作用？在探索C9orf72突变如何导致疾病的各个方面都取得了巨大进展。许多新的实验模型已经建立，并在强大的遗传筛选中得到释放。对小鼠和人类患者样本（包括iPS衍生的神经元）的研究为致病机制提供了前所未有的见解。三个主要的假设已经出现，并仍在该领域激烈辩论。这包括：1）由于C9orf72蛋白丰度的降低及其执行其仍然未知的细胞作用的能力的丧失：2）来自双向转录的正义（GGGGCC）和反义（GGCCCC）转录物的RNA毒性，其积累在RNA灶中并可能隔离关键的RNA结合蛋白; 3）来自二肽重复蛋白质的蛋白毒性，所述二肽重复蛋白质是由扩增的核苷酸重复的非常规翻译形式产生的。在这里，我们回顾支持和反对这三个假设的证据。我们还提出了额外的实验和考虑因素，我们提出这些实验和考虑因素将有助于澄清哪些机制对驱动疾病最重要，因此在开发治疗干预措施时最关键。
The discovery of C9orf72 mutations as the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has awakened a surge of interest in deciphering how mutations in this mysterious gene cause disease and what can be done to stop it. C9orf72 harbors a hexanucleotide repeat, GGGGCC, in a non-coding region of the gene and a massive expansion of this repeat causes ALS, FTD, or both (FTD/ALS). Many questions lie ahead. What does this gene normally do? What is the consequence of an enormous GGGGCC repeat expansion on that gene’s function? Could that hexanucleotide repeat expansion have additional pathological actions unrelated to C9orf72 function? There has been tremendous progress on all fronts in the quest to define how C9orf72 mutations cause disease. Many new experimental models have been constructed and unleashed in powerful genetic screens. Studies in mouse and human patient samples, including iPS-derived neurons, have provided unprecedented insights into pathogenic mechanisms. Three major hypotheses have emerged and are still being hotly debated in the field. These include 1) loss of function owing to decrease in the abundance of C9orf72 protein and its ability to carryout its still unknown cellular role; 2) RNA toxicity from bidirectionally transcribed sense (GGGGCC) and antisense (GGCCCC) transcripts that accumulate in RNA foci and might sequester critical RNA-binding proteins; 3) proteotoxicity from dipeptide repeat proteins produced by an unconventional form of translation from the expanded nucleotide repeats. Here we review the evidence in favor and against each of these three hypotheses. We also suggest additional experiments and considerations that we propose will help clarify which mechanism(s) are most important for driving disease and therefore most critical for considering during the development of therapeutic interventions.
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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
与C9ORF72扩张相关的额颞叶变性和运动神经元疾病中二肽重复蛋白的脑分布。
影响因子：
7.1
作者：
Davidson YS;Barker H;Robinson AC;Thompson JC;Harris J;Troakes C;Smith B;Al-Saraj S;Shaw C;Rollinson S;Masuda-Suzukake M;Hasegawa M;Pickering-Brown S;Snowden JS;Mann DM
通讯作者：
Mann DM
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
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
DOI：
10.1126/science.aaa9344
发表时间：
2015-06-05
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chew J;Gendron TF;Prudencio M;Sasaguri H;Zhang YJ;Castanedes-Casey M;Lee CW;Jansen-West K;Kurti A;Murray ME;Bieniek KF;Bauer PO;Whitelaw EC;Rousseau L;Stankowski JN;Stetler C;Daughrity LM;Perkerson EA;Desaro P;Johnston A;Overstreet K;Edbauer D;Rademakers R;Boylan KB;Dickson DW;Fryer JD;Petrucelli L
通讯作者：
Petrucelli L