Widespread intron retention impairs protein homeostasis in C9orf72 ALS brains.
Widespread intron retention impairs protein homeostasis in C9orf72 ALS brains.
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DOI：
10.1101/gr.265298.120
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发表时间：
2020-12
期刊：
影响因子：
7
通讯作者：
Rio DC
中科院分区：
文献类型：
--
作者：
Wang Q;Conlon EG;Manley JL;Rio DC
C9 orf 72（C9）中的GGGGCC六核苷酸扩增是肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的最常见已知原因，但对C9如何适应ALS/FTD病理学的更广泛背景的清晰理解仍然缺乏。已知源自C9重复序列的重复RNA会将剪接调节因子hnRNPH隔离成不溶性聚集体，导致异常的选择性剪接。此外，在C9和散发性ALS/FTD患者中观察到hnRNPH不溶性和一组稳健靶点的剪接改变相关，表明沿着该轴的变化是疾病发病机制的核心特征。在这里，我们以前未分类的RNA剪接缺陷的特点涉及广泛的内含子保留影响近2000个成绩单在C9 ALS/FTD的大脑表现出大量的隔离，不溶性hnRNPH。这些内含子保留事件似乎不会改变受影响的转录本的总体表达水平，而是蛋白质编码区。这些保留的内含子影响预测参与C9以及散发性ALS/FTD病因学的多个细胞途径中的转录物，包括蛋白酶体和自噬系统。保留的内含子前体mRNA显示出许多特征，包括hnRNPH结合的剪接增强子基序的富集和G-四链体（G-Q）形成的倾向，将有缺陷的剪接直接与大量的隔离的hnRNPH联系起来。总之，我们的研究结果揭示了以前未检测到的剪接缺陷在高不溶性hnRNPH相关的C9 ALS大脑，这表明有效的RNA结合蛋白剂量和蛋白质质量控制之间的反馈C9，也许所有的ALS/FTD。
The GGGGCC hexanucleotide expansion in C9orf72 (C9) is the most frequent known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet a clear understanding of how C9 fits into the broader context of ALS/FTD pathology has remained lacking. The repetitive RNA derived from the C9 repeat is known to sequester hnRNPH, a splicing regulator, into insoluble aggregates, resulting in aberrant alternative splicing. Furthermore, hnRNPH insolubility and altered splicing of a robust set of targets have been observed to correlate in C9 and sporadic ALS/FTD patients alike, suggesting that changes along this axis are a core feature of disease pathogenesis. Here, we characterize previously uncategorized RNA splicing defects involving widespread intron retention affecting almost 2000 transcripts in C9ALS/FTD brains exhibiting a high amount of sequestered, insoluble hnRNPH. These intron retention events appear not to alter overall expression levels of the affected transcripts but rather the protein-coding regions. These retained introns affect transcripts in multiple cellular pathways predicted to be involved in C9 as well as sporadic ALS/FTD etiology, including the proteasomal and autophagy systems. The retained intron pre-mRNAs display a number of characteristics, including enrichment of hnRNPH-bound splicing enhancer motifs and a propensity for G-quadruplex (G-Q) formation, linking the defective splicing directly to high amounts of sequestered hnRNPH. Together, our results reveal previously undetected splicing defects in high insoluble hnRNPH-associated C9ALS brains, suggesting a feedback between effective RNA-binding protein dosage and protein quality control in C9, and perhaps all, ALS/FTD.
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DOI：
10.1126/science.aaa3650
发表时间：
2015-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cirulli ET;Lasseigne BN;Petrovski S;Sapp PC;Dion PA;Leblond CS;Couthouis J;Lu YF;Wang Q;Krueger BJ;Ren Z;Keebler J;Han Y;Levy SE;Boone BE;Wimbish JR;Waite LL;Jones AL;Carulli JP;Day-Williams AG;Staropoli JF;Xin WW;Chesi A;Raphael AR;McKenna-Yasek D;Cady J;Vianney de Jong JM;Kenna KP;Smith BN;Topp S;Miller J;Gkazi A;FALS Sequencing Consortium;Al-Chalabi A;van den Berg LH;Veldink J;Silani V;Ticozzi N;Shaw CE;Baloh RH;Appel S;Simpson E;Lagier-Tourenne C;Pulst SM;Gibson S;Trojanowski JQ;Elman L;McCluskey L;Grossman M;Shneider NA;Chung WK;Ravits JM;Glass JD;Sims KB;Van Deerlin VM;Maniatis T;Hayes SD;Ordureau A;Swarup S;Landers J;Baas F;Allen AS;Bedlack RS;Harper JW;Gitler AD;Rouleau GA;Brown R;Harms MB;Cooper GM;Harris T;Myers RM;Goldstein DB
通讯作者：
Goldstein DB
影响因子：
16.2
作者：
Kim HJ;Taylor JP
通讯作者：
Taylor JP
影响因子：
48
作者：
Katz, Yarden;Wang, Eric T.;Airoldi, Edoardo M.;Burge, Christopher B.
通讯作者：
Burge, Christopher B.
影响因子：
10.5
作者：
Conlon EG;Manley JL
通讯作者：
Manley JL
影响因子：
7.7
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
通讯作者：
Manley JL