Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS.
Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS.
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DOI：
10.1016/j.neuron.2013.02.004
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发表时间：
2013-02-20
期刊：
影响因子：
16.2
通讯作者：
Petrucelli L
中科院分区：
文献类型：
--
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
额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS）是具有临床、遗传和神经病理学重叠的毁灭性神经退行性疾病。C9ORF72非编码区的六核苷酸（GGGGCC）重复扩增是FTD和ALS（c9FTD/ALS）的主要遗传原因。GGGGCC重复序列的RNA结构使这些转录本易受一种非常规翻译机制——重复相关非ATG（RAN）翻译的影响。针对假定的GGGGCC重复RAN翻译肽段产生的抗体（抗 - C9RANT）在c9FTD/ALS病例的脑匀浆中检测到高分子量、不溶性物质以及整个中枢神经系统的神经元包涵体。在其他神经退行性疾病（包括CAG重复疾病）或c9FTD/ALS的外周组织中未发现C9RANT免疫反应性。C9RANT对c9FTD/ALS的特异性是这种FTD和ALS最常见病因的一个潜在生物标志物。这些发现对针对RAN翻译肽段及其聚集以及产生它们所必需的RNA结构的治疗策略具有重要意义。
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders with clinical, genetic, and neuropathological overlap. Hexanucleotide (GGGGCC) repeat expansions in a non-coding region of C9ORF72 are the major genetic cause of FTD and ALS (c9FTD/ALS). The RNA structure of GGGGCC repeats renders these transcripts susceptible to an unconventional mechanism of translation – repeat-associated non-ATG (RAN) translation. Antibodies generated against putative GGGGCC repeat RAN translated peptides (anti-C9RANT) detected high molecular weight, insoluble material in brain homogenates, and neuronal inclusions throughout the central nervous system of c9FTD/ALS cases. C9RANT immunoreactivity was not found in other neurodegenerative diseases, including CAG repeat disorders, or in peripheral tissues of c9FTD/ALS. The specificity of C9RANT for c9FTD/ALS is a potential biomarker for this most common cause of FTD and ALS. These findings have significant implications for treatment strategies directed at RAN translated peptides and their aggregation, and the RNA structures necessary for their production.
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