Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism.
Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism.
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DOI：
10.7554/elife.37754
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发表时间：
2018-07-13
期刊：
影响因子：
7.7
通讯作者：
Manley JL
中科院分区：
文献类型：
--
作者：
Conlon EG;Fagegaltier D;Agius P;Davis-Porada J;Gregory J;Hubbard I;Kang K;Kim D;New York Genome Center ALS Consortium;Phatnani H;Shneider NA;Manley JL
肌萎缩侧索硬化症(ALS)和额颞叶痴呆(FTD)是疾病谱的两端，具有共同的临床、遗传和病理特征。这些包括几乎无处不在的RNA结合蛋白(RBP)TDP-43的病理包涵体，以及C9ORF72(C9)基因中经常存在的GGGGCC扩增。此前，我们报道了hnRNP H的分离改变了C9ALS患者目标转录本的剪接(Conlon等人，2016)。在这里，我们表明，这个特征也发生在50例死后散发性的、非C9 ALS/FTD脑中。此外，同样令人惊讶的是，这些“类C9”脑中也含有相应数量的不溶性TDP-43，以及其他几种与疾病相关的限制性商业惯例，这与广泛存在的全球剪接缺陷有关。最后，我们发现，与实际的C9ALS患者一样，类似C9的散发性患者更有可能发生FTD。我们认为C9和散发性ALS/FTD之间的这些意想不到的联系定义了这种疾病谱中的一种共同机制。
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of a disease spectrum with shared clinical, genetic and pathological features. These include near ubiquitous pathological inclusions of the RNA-binding protein (RBP) TDP-43, and often the presence of a GGGGCC expansion in the C9ORF72 (C9) gene. Previously, we reported that the sequestration of hnRNP H altered the splicing of target transcripts in C9ALS patients (Conlon et al., 2016). Here, we show that this signature also occurs in half of 50 postmortem sporadic, non-C9 ALS/FTD brains. Furthermore, and equally surprisingly, these ‘like-C9’ brains also contained correspondingly high amounts of insoluble TDP-43, as well as several other disease-related RBPs, and this correlates with widespread global splicing defects. Finally, we show that the like-C9 sporadic patients, like actual C9ALS patients, were much more likely to have developed FTD. We propose that these unexpected links between C9 and sporadic ALS/FTD define a common mechanism in this disease spectrum.