Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43.
Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43.
复制标题
DOI：
10.1038/nn.2779
复制
发表时间：
2011-04
影响因子：
25
通讯作者：
Cleveland, Don W.
中科院分区：
文献类型：
--
作者：
Polymenidou, Magdalini;Lagier-Tourenne, Clotilde;Hutt, Kasey R.;Huelga, Stephanie C.;Moran, Jacqueline;Liang, Tiffany Y.;Ling, Shuo-Chien;Sun, Eveline;Wancewicz, Edward;Mazur, Curt;Kordasiewicz, Holly;Sedaghat, Yalda;Donohue, John Paul;Shiue, Lily;Bennett, C. Frank;Yeo, Gene W.;Cleveland, Don W.
使用交联和免疫沉淀结合高通量测序来鉴定6，304个基因内的结合位点作为TDP-43的脑RNA靶点，TDP-43是一种RNA结合蛋白，当突变时会导致肌萎缩性侧索硬化症（ALS）。使用大规模平行测序和剪接敏感性连接阵列显示，在用反义寡核苷酸耗尽小鼠成年脑中的TDP-43后，601种mRNA的水平发生了变化（包括Fus/Tls、颗粒蛋白前体和编码神经退行性疾病相关蛋白的其他转录物），并检测到965种改变的剪接事件（包括颗粒蛋白前体的受体分拣蛋白）。其水平因TDP-43的减少而最耗尽的RNA来源于具有非常长的内含子的基因，并且其编码参与突触活性的蛋白质。最后，TDP-43被发现自动调节其合成，部分通过直接结合和增强其自身转录物3′非翻译区内内含子的剪接，从而触发无义介导的RNA降解。(147字）
Cross-linking and immunoprecipitation coupled with high-throughput sequencing was used to identify binding sites within 6,304 genes as the brain RNA targets for TDP-43, an RNA binding protein which when mutated causes Amyotrophic Lateral Sclerosis (ALS). Use of massively parallel sequencing and splicing-sensitive junction arrays revealed that levels of 601 mRNAs are changed (including Fus/Tls, progranulin, and other transcripts encoding neurodegenerative disease-associated proteins) and 965 altered splicing events are detected (including in sortilin, the receptor for progranulin), following depletion of TDP-43 from mouse adult brain with antisense oligonucleotides. RNAs whose levels are most depleted by reduction in TDP-43 are derived from genes with very long introns and which encode proteins involved in synaptic activity. Lastly, TDP-43 was found to auto-regulate its synthesis, in part by directly binding and enhancing splicing of an intron within the 3′ untranslated region of its own transcript, thereby triggering nonsense mediated RNA degradation. (147 words)
登录
查看更多内容
影响因子：
64.5
作者：
Cooper TA;Wan L;Dreyfuss G
通讯作者：
Dreyfuss G
影响因子：
64.8
作者：
Cruts, Marc;Gijselinck, Ilse;Van Broeckhoven, Christine
通讯作者：
Van Broeckhoven, Christine
影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.
DOI：
10.1073/pnas.1008227107
发表时间：
2010-07-27
影响因子：
11.1
作者：
Ling, Shuo-Chien;Albuquerque, Claudio P.;Cleveland, Don W.
通讯作者：
Cleveland, Don W.
影响因子：
5.4
作者：
Buratti, Emanuele;De Conti, Laura;Baralle, Francisco
通讯作者：
Baralle, Francisco