The Spectrum of C9orf72-mediated Neurodegeneration and Amyotrophic Lateral Sclerosis.
The Spectrum of C9orf72-mediated Neurodegeneration and Amyotrophic Lateral Sclerosis.
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DOI：
10.1007/s13311-015-0342-1
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发表时间：
2015-04
影响因子：
5.7
通讯作者：
Shaw, Pamela J.
中科院分区：
文献类型：
--
作者：
Cooper-Knock, Johnathan;Kirby, Janine;Highley, Robin;Shaw, Pamela J.
关键词：
C9orf72基因中的六核苷酸重复扩增是肌萎缩侧索硬化症和额颞叶痴呆最常见的基因变异，这一发现开启了一个快速发展的领域，可能为理解和治疗这些毁灭性疾病带来期待已久的进展。在这篇综述中，我们描述了与C9orf72扩增相关的各种临床和病理表型，其范围不仅包括肌萎缩侧索硬化症和额颞叶痴呆，还更广泛地涵盖了神经退行性变。接下来，我们退后一步，在分子水平上总结了目前对C9orf72扩增及其蛋白产物的理解。有三种机制较为突出：由重复序列转录的RNA直接介导的毒性；由重复序列翻译的二肽重复蛋白介导的毒性；以及C9orf72外显子序列转录减少导致的单倍体不足。最近一系列令人兴奋的进展描述了二肽重复蛋白如何干扰核仁在RNA结合蛋白成熟和核糖体生成中的正常作用。重要的是，这些机制不太可能相互排斥。我们提请注意，在将致病机制归因于C9orf72相关疾病时，不应忽视与其他无重复扩增的基因变异在临床和病理上的相似性。最后，考虑到对患者护理的影响，我们讨论了针对有和无疾病家族史患者的基因筛查的当前实践，以及迄今为止报道的最有希望的治疗进展。
本文的在线版本（doi:10.1007/s13311 - 015 - 0342 - 1）包含补充材料，可供授权用户使用。
The discovery that a hexanucleotide repeat expansion in C9orf72 is the most numerous genetic variant of both amyotrophic lateral sclerosis and frontotemporal dementia has opened a rapidly growing field, which may provide long hoped for advances in the understanding and treatment of these devastating diseases. In this review we describe the various phenotypes, clinical and pathological, associated with expansion of C9orf72, which go beyond amyotrophic lateral sclerosis and frontotemporal dementia to include neurodegeneration more broadly. Next we take a step back and summarize the current understanding of the C9orf72 expansion and its protein products at a molecular level. Three mechanisms are prominent: toxicity mediated directly by RNA transcribed from the repeat; toxicity mediated by dipeptide repeat proteins translated from the repeat sequence; and haploinsufficiency resulting from reduced transcription of the C9orf72 exonic sequence. A series of exciting advances have recently described how dipeptide repeat proteins might interfere with the normal role of the nucleolus in maturation of RNA binding proteins and in production of ribosomes. Importantly, these mechanisms are unlikely to be mutually exclusive. We draw attention to the fact that clinical and pathological similarities to other genetic variants without a repeat expansion must not be overlooked in ascribing a pathogenic mechanism to C9orf72-disease. Finally, with a view to impact on patient care, we discuss current practice with respect to genetic screening in patients with and without a family history of disease, and the most promising developments towards therapy that have been reported to date. The online version of this article (doi:10.1007/s13311-015-0342-1) contains supplementary material, which is available to authorized users.
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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：
7.8
作者：
Bubulya, PA;Prasanth, KV;Spector, DL
通讯作者：
Spector, DL
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：
14.5
作者：
Chio, Adriano;Borghero, Giuseppe;Sabatelli, Mario
通讯作者：
Sabatelli, Mario
影响因子：
12.7
作者：
Al-Sarraj, Safa;King, Andrew;Shaw, Christopher E.
通讯作者：
Shaw, Christopher E.