TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD.
TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD.
复制标题
DOI：
10.1038/s41593-018-0113-5
复制
发表时间：
2018-04
影响因子：
25
通讯作者：
Sreedharan J
中科院分区：
文献类型：
--
作者：
White MA;Kim E;Duffy A;Adalbert R;Phillips BU;Peters OM;Stephenson J;Yang S;Massenzio F;Lin Z;Andrews S;Segonds-Pichon A;Metterville J;Saksida LM;Mead R;Ribchester RR;Barhomi Y;Serre T;Coleman MP;Fallon JR;Bussey TJ;Brown RH Jr;Sreedharan J
肌萎缩性侧索硬化-额颞叶痴呆（ALS-FTD）是一种以TDP-43病理学为特征的破坏性疾病谱。了解TDP-43如何促进神经变性将有助于指导治疗工作。在这里，我们创造了一种新的TDP-43基因敲入小鼠，在内源性小鼠Tardbp基因中具有人类等效突变。TDP-43 Q331 K小鼠表现出认知功能障碍和缺乏小清蛋白中间神经元。重要的是，TDP-43自身调节受到干扰，导致TDP-43功能的获得，以及另一个关键痴呆基因Mapt的剪接改变。此外，一种按受差异影响的突变小鼠的表型对转录组数据进行分层的新方法揭示了471种与行为改善相关的变化。这些变化包括两种已知的神经变性修饰剂Atxn 2和Arid 4a的下调，以及髓鞘形成和翻译基因的上调。通过鼠Tardbp中的一个碱基变化，本研究确定TDP-43误调节为可能支持ALS-FTD的致病机制，并利用表型异质性产生神经退行性疾病的候选抑制因子。
Amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) constitutes a devastating disease spectrum characterised by TDP-43 pathology. Understanding how TDP-43 contributes to neurodegeneration will help direct therapeutic efforts. Here, we have created a novel TDP-43 knock-in mouse with a human-equivalent mutation in the endogenous mouse Tardbp gene. TDP-43Q331K mice demonstrate cognitive dysfunction and a paucity of parvalbumin interneurons. Critically, TDP-43 autoregulation is perturbed leading to a gain of TDP-43 function, and altered splicing of Mapt, another pivotal dementia gene. Furthermore, a novel approach to stratify transcriptomic data by phenotype in differentially affected mutant mice reveals 471 changes linked with improved behaviour. These changes include downregulation of two known modifiers of neurodegeneration, Atxn2 and Arid4a, and upregulation of myelination and translation genes. With one base change in murine Tardbp, this study identifies TDP-43 misregulation as a pathogenic mechanism that may underpin ALS-FTD, and exploits phenotypic heterogeneity to yield candidate suppressors of neurodegenerative disease.
登录
查看更多内容
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：
25
作者：
Kang, Shin H.;Li, Ying;Fukaya, Masahiro;Lorenzini, Ileana;Cleveland, Don W.;Ostrow, Lyle W.;Rothstein, Jeffrey D.;Bergles, Dwight E.
通讯作者：
Bergles, Dwight E.
影响因子：
4.8
作者：
Johnson, Brian S.;Snead, David;Gitler, Aaron D.
通讯作者：
Gitler, Aaron D.
影响因子：
--
作者：
Borroni, B;Yancopoulou, D;Spillantini, MG
通讯作者：
Spillantini, MG
影响因子：
7.1
作者：
Behrouzi R;Liu X;Wu D;Robinson AC;Tanaguchi-Watanabe S;Rollinson S;Shi J;Tian J;Hamdalla HH;Ealing J;Richardson A;Jones M;Pickering-Brown S;Davidson YS;Strong MJ;Hasegawa M;Snowden JS;Mann DM
通讯作者：
Mann DM