Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis.
Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis.
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DOI：
10.15252/embj.201798684
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发表时间：
2018-06-01
期刊：
影响因子：
--
通讯作者：
Acevedo-Arozena A
中科院分区：
文献类型：
--
作者：
Fratta P;Sivakumar P;Humphrey J;Lo K;Ricketts T;Oliveira H;Brito-Armas JM;Kalmar B;Ule A;Yu Y;Birsa N;Bodo C;Collins T;Conicella AE;Mejia Maza A;Marrero-Gagliardi A;Stewart M;Mianne J;Corrochano S;Emmett W;Codner G;Groves M;Fukumura R;Gondo Y;Lythgoe M;Pauws E;Peskett E;Stanier P;Teboul L;Hallegger M;Calvo A;Chiò A;Isaacs AM;Fawzi NL;Wang E;Housman DE;Baralle F;Greensmith L;Buratti E;Plagnol V;Fisher EM;Acevedo-Arozena A
TDP-43（由基因TARDBP编码）是一种RNA结合蛋白，对肌萎缩侧索硬化症（ALS）的发病机制至关重要。然而，TARDBP突变如何触发发病机制仍不清楚。在这里，我们使用在内源性Tardbp中携带点突变的新型小鼠突变体来剖析TDP-43在体外和体内生理水平上的功能。有趣的是，我们发现TDP-43的C末端结构域内的突变导致剪接功能的获得。使用两种不同的菌株，我们能够区分TDP-43功能丧失和功能获得效应。TDP-43在这些小鼠中的功能获得效应揭示了由TDP-43控制的一类新的剪接事件，称为“跳跃”外显子，其中组成型外显子的跳跃导致基因表达的变化。在体内，内源性Tardbp的这种功能获得性突变导致成人发作的神经肌肉表型，伴有运动神经元丢失和神经退行性变化。此外，我们已经验证了ALS患者来源细胞中的剪接功能增益和跳跃外显子。我们的研究结果提供了一种新的致病机制，并强调了TDP-43功能获得和功能丧失如何不同地影响RNA加工，表明它们可能在不同的疾病阶段起作用。
TDP‐43 (encoded by the gene TARDBP) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP‐43 function at physiological levels both in vitro and in vivo. Interestingly, we find that mutations within the C‐terminal domain of TDP‐43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP‐43 loss‐ and gain‐of‐function effects. TDP‐43 gain‐of‐function effects in these mice reveal a novel category of splicing events controlled by TDP‐43, referred to as “skiptic” exons, in which skipping of constitutive exons causes changes in gene expression. In vivo, this gain‐of‐function mutation in endogenous Tardbp causes an adult‐onset neuromuscular phenotype accompanied by motor neuron loss and neurodegenerative changes. Furthermore, we have validated the splicing gain‐of‐function and skiptic exons in ALS patient‐derived cells. Our findings provide a novel pathogenic mechanism and highlight how TDP‐43 gain of function and loss of function affect RNA processing differently, suggesting they may act at different disease stages.
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影响因子：
2.7
作者：
Humphrey J;Emmett W;Fratta P;Isaacs AM;Plagnol V
通讯作者：
Plagnol V
影响因子：
4.8
作者：
Huppertz, Ina;Attig, Jan;D'Ambrogio, Andrea;Easton, Laura E.;Sibley, Christopher R.;Sugimoto, Yoichiro;Tajnik, Mojca;Koenig, Julian;Ule, Jernej
通讯作者：
Ule, Jernej
影响因子：
14.9
作者：
Koyama A;Sugai A;Kato T;Ishihara T;Shiga A;Toyoshima Y;Koyama M;Konno T;Hirokawa S;Yokoseki A;Nishizawa M;Kakita A;Takahashi H;Onodera O
通讯作者：
Onodera O
DOI：
10.1007/978-1-60327-019-9_8
发表时间：
2009-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Gardiner, Wendy J K;Teboul, Lydia
通讯作者：
Teboul, Lydia
影响因子：
12.7
作者：
Mitchell JC;McGoldrick P;Vance C;Hortobagyi T;Sreedharan J;Rogelj B;Tudor EL;Smith BN;Klasen C;Miller CC;Cooper JD;Greensmith L;Shaw CE
通讯作者：
Shaw CE