TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.
TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.
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肌萎缩性侧索硬化和额颞痴呆的TIA1突变促进相位分离并改变应激颗粒动力学。
DOI：
10.1016/j.neuron.2017.07.025
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发表时间：
2017-08-16
期刊：
影响因子：
16.2
通讯作者：
Rademakers R
中科院分区：
文献类型：
--
作者：
Mackenzie IR;Nicholson AM;Sarkar M;Messing J;Purice MD;Pottier C;Annu K;Baker M;Perkerson RB;Kurti A;Matchett BJ;Mittag T;Temirov J;Hsiung GR;Krieger C;Murray ME;Kato M;Fryer JD;Petrucelli L;Zinman L;Weintraub S;Mesulam M;Keith J;Zivkovic SA;Hirsch-Reinshagen V;Roos RP;Züchner S;Graff-Radford NR;Petersen RC;Caselli RJ;Wszolek ZK;Finger E;Lippa C;Lacomis D;Stewart H;Dickson DW;Kim HJ;Rogaeva E;Bigio E;Boylan KB;Taylor JP;Rademakers R
肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）是年龄相关的神经退行性疾病，具有共同的遗传病因和重叠的临床和病理特征。在这里，我们研究了一个新的ALS/FTD家族，并确定了T细胞限制性细胞内抗原-1（TIA 1）的低复杂性结构域（LCD）中的P362 L突变。随后的遗传关联分析显示，与对照组相比，ALS患者的TIA 1 LCD突变负担增加（P = 8.7×10−6）。五个TIA 1突变携带者的尸检神经病理学表现出一致的病理学特征，具有许多圆形、透明、TAR DNA结合蛋白43（TDP-43）阳性包涵体。TIA 1突变显著增加了TIA 1蛋白发生相变的倾向。在活细胞中，TIA 1突变延迟了应激颗粒（SG）的分解，并促进了含有TDP-43的非动态SG的积累。此外，SG中的TDP-43变得不那么移动的和不溶性。ALS/FTD中TIA 1突变的鉴定强化了RNA代谢和SG动力学在ALS/FTD发病机制中的重要性。
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low complexity domain (LCD) of T-cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (P = 8.7×10−6). Postmortem neuropathology of five TIA1 mutations carriers showed a consistent pathological signature with numerous round, hyaline, TAR DNA-binding protein 43 (TDP-43)-positive inclusions. TIA1 mutations significantly increased the propensity of TIA1 protein to undergo phase transition. In live cells, TIA1 mutations delayed stress granule (SG) disassembly and promoted the accumulation of non-dynamic SGs that harbored TDP-43. Moreover, TDP-43 in SGs became less mobile and insoluble. The identification of TIA1 mutations in ALS/FTD reinforces the importance of RNA metabolism and SG dynamics in ALS/FTD pathogenesis.
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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：
11.2
作者：
Hackman, Peter;Sarparanta, Jaakko;Udd, Bjarne
通讯作者：
Udd, Bjarne
影响因子：
25
作者：
Johnson, Janel O.;Pioro, Erik P.;Boehringer, Ashley;Chia, Ruth;Feit, Howard;Renton, Alan E.;Pliner, Hannah A.;Abramzon, Yevgeniya;Marangi, Giuseppe;Winborn, Brett J.;Gibbs, J. Raphael;Nalls, Michael A.;Morgan, Sarah;Shoai, Maryam;Hardy, John;Pittman, Alan;Orrell, Richard W.;Malaspina, Andrea;Sidle, Katie C.;Fratta, Pietro;Harms, Matthew B.;Baloh, Robert H.;Pestronk, Alan;Weihl, Conrad C.;Rogaeva, Ekaterina;Zinman, Lorne;Drory, Vivian E.;Borghero, Giuseppe;Mora, Gabriele;Calvo, Andrea;Rothstein, Jeffrey D.;Drepper, Carsten;Sendtner, Michael;Singleton, Andrew B.;Taylor, J. Paul;Cookson, Mark R.;Restagno, Gabriella;Sabatelli, Mario;Bowser, Robert;Chio, Adriano;Traynor, Bryan J.
通讯作者：
Traynor, Bryan J.
影响因子：
12.7
作者：
Neumann M;Kwong LK;Lee EB;Kremmer E;Flatley A;Xu Y;Forman MS;Troost D;Kretzschmar HA;Trojanowski JQ;Lee VM
通讯作者：
Lee VM
DOI：
10.1083/jcb.106.4.1131
发表时间：
1988-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Collier NC;Heuser J;Levy MA;Schlesinger MJ
通讯作者：
Schlesinger MJ