Prematurely terminated intron-retaining mRNAs invade axons in SFPQ null-driven neurodegeneration and are a hallmark of ALS.
Prematurely terminated intron-retaining mRNAs invade axons in SFPQ null-driven neurodegeneration and are a hallmark of ALS.
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DOI：
10.1038/s41467-022-34331-4
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发表时间：
2022-11-22
影响因子：
16.6
通讯作者：
Houart, Corinne
中科院分区：
文献类型：
--
作者：
Taylor, Richard;Hamid, Fursham;Fielding, Triona;Gordon, Patricia M.;Maloney, Megan;Makeyev, Eugene, V;Houart, Corinne
SFPQ的丧失是ALS中运动变性的标志，并且当发生在胚胎发生期间时阻止运动神经元的成熟。在这里，我们表明，在斑马鱼，发展中的运动神经元缺乏SFPQ表现出轴突延伸，分支和突触发育缺陷，退化之前。亚细胞转录组学揭示，神经元中SFPQ的缺失产生一组复杂的异常内含子保留（IR）转录本，其编码神经元特异性蛋白质并在神经突中积累。这些局部IR mRNA中的一些在保留内含子（PreT-IR）内过早终止。在体外和体内，PreT-IR mRNA经历内含子聚腺苷酸化、核输出并定位于神经突。我们发现这些IR和PreT-IR mRNA在来自家族性和散发性ALS患者的组织的RNAseq数据集中富集。SFPQ缺失的神经元和ALS之间的这种共享签名在功能上暗示SFPQ与疾病有关，并表明以神经突为中心的可变剪接异构体的扰动驱动神经退行性过程。剪接因子SFPQ的核耗竭和细胞质积累是ALS的标志。在这里，作者证明了SFPQ的丢失与ALS模型和组织中富含内含子保留mRNA的神经突的出现之间的关系。
Loss of SFPQ is a hallmark of motor degeneration in ALS and prevents maturation of motor neurons when occurring during embryogenesis. Here, we show that in zebrafish, developing motor neurons lacking SFPQ exhibit axon extension, branching and synaptogenesis defects, prior to degeneration. Subcellular transcriptomics reveals that loss of SFPQ in neurons produces a complex set of aberrant intron-retaining (IR) transcripts coding for neuron-specific proteins that accumulate in neurites. Some of these local IR mRNAs are prematurely terminated within the retained intron (PreT-IR). PreT-IR mRNAs undergo intronic polyadenylation, nuclear export, and localise to neurites in vitro and in vivo. We find these IR and PreT-IR mRNAs enriched in RNAseq datasets of tissue from patients with familial and sporadic ALS. This shared signature, between SFPQ-depleted neurons and ALS, functionally implicates SFPQ with the disease and suggests that neurite-centred perturbation of alternatively spliced isoforms drives the neurodegenerative process. Nuclear depletion and cytoplasmic accumulation of splicing factor SFPQ are hallmarks of ALS. Here the authors demonstrate a relationship between loss of SFPQ and the emergence in neurites of intron-retaining mRNAs enriched in ALS models and tissues.
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影响因子：
16.6
作者：
Gordon PM;Hamid F;Makeyev EV;Houart C
通讯作者：
Houart C
影响因子：
7
作者：
Braunschweig U;Barbosa-Morais NL;Pan Q;Nachman EN;Alipanahi B;Gonatopoulos-Pournatzis T;Frey B;Irimia M;Blencowe BJ
通讯作者：
Blencowe BJ
DOI：
10.1073/pnas.2113929118
发表时间：
2021-10-26
影响因子：
11.1
作者：
Glock C;Biever A;Tushev G;Nassim-Assir B;Kao A;Bartnik I;Tom Dieck S;Schuman EM
通讯作者：
Schuman EM
影响因子：
64.5
作者：
Giorgi, Corinna;Yeo, Gene W.;Moore, Melissa J.
通讯作者：
Moore, Melissa J.
影响因子：
16.2
作者：
Kanai, Y;Dohmae, N;Hirokawa, N
通讯作者：
Hirokawa, N