p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR).
p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR).
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p53是驱动C9orf72 poly（PR）引起的神经退行性变的中枢调节因子。
DOI：
10.1016/j.cell.2020.12.025
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发表时间：
2021-02-04
期刊：
影响因子：
64.5
通讯作者：
Gitler AD
中科院分区：
文献类型：
--
作者：
Maor-Nof M;Shipony Z;Lopez-Gonzalez R;Nakayama L;Zhang YJ;Couthouis J;Blum JA;Castruita PA;Linares GR;Ruan K;Ramaswami G;Simon DJ;Nof A;Santana M;Han K;Sinnott-Armstrong N;Bassik MC;Geschwind DH;Tessier-Lavigne M;Attardi LD;Lloyd TE;Ichida JK;Gao FB;Greenleaf WJ;Yokoyama JS;Petrucelli L;Gitler AD
ALS和FTD最常见的遗传原因是C9 orf 72基因中的GGGGCC重复扩增。我们开发了一个平台来询问变性过程中神经元内的染色质可及性景观和转录程序。我们提供的证据表明，神经元表达的二肽重复蛋白聚（脯氨酸-精氨酸），从C9 orf 72重复扩增翻译，激活一个高度特异性的转录程序，例如一个单一的转录因子，p53。在C9 orf 72小鼠模型中，在小鼠中抑制p53完全拯救了神经元免于变性，并显著增加了存活率。p53减少还挽救了聚（甘氨酸-精氨酸）引起的轴突变性，增加了C9 orf 72 ALS/FTD患者iPSC衍生运动神经元的存活率，并减轻了C9 orf 72苍蝇模型中的神经变性。我们发现p53激活了下游转录程序，包括驱动神经退行性变的Puma。这些数据表明，通过转录因子结合事件动态调节的神经退行性机制，并提供了一个框架，适用于染色质可及性和转录程序配置文件的神经退行性。与ALS和FTD相关的C9 orf 72突变激活了一种特异性转录程序，该程序在多种C9 orf 72模型中会聚于p53以驱动神经退行性变
The most common genetic cause of ALS and FTD is a GGGGCC repeat expansion in the C9orf72 gene. We developed a platform to interrogate the chromatin accessibility landscape and transcriptional program within neurons during degeneration. We provide evidence that neurons expressing the dipeptide repeat protein poly(proline-arginine), translated from the C9orf72 repeat expansion, activate a highly specific transcriptional program, exemplified by a single transcription factor, p53. Ablating p53 in mice completely rescued neurons from degeneration and markedly increased survival in a C9orf72 mouse model. p53 reduction also rescued axonal degeneration caused by poly(glycine-arginine), increased survival of C9orf72 ALS/FTD patient iPSC-derived motor neurons, and mitigated neurodegeneration in a C9orf72 fly model. We show that p53 activates a downstream transcriptional program, including Puma, which drives neurodegeneration. These data demonstrate a neurodegenerative mechanism dynamically regulated through transcription factor binding events and provide a framework to apply chromatin accessibility and transcription program profiles to neurodegeneration. C9orf72 mutations associated with ALS and FTD activates a specific transcriptional program that converges on p53 to drive neurodegeneration in multiple C9orf72 models
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影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
通讯作者：
Petrucelli L
与C9ORF72扩张相关的额颞叶变性和运动神经元疾病中二肽重复蛋白的脑分布。
影响因子：
7.1
作者：
Davidson YS;Barker H;Robinson AC;Thompson JC;Harris J;Troakes C;Smith B;Al-Saraj S;Shaw C;Rollinson S;Masuda-Suzukake M;Hasegawa M;Pickering-Brown S;Snowden JS;Mann DM
通讯作者：
Mann DM
影响因子：
25
作者：
Chesi, Alessandra;Staahl, Brett T.;Jovicic, Ana;Couthouis, Julien;Fasolino, Maria;Raphael, Alya R.;Yamazaki, Tomohiro;Elias, Laura;Polak, Meraida;Kelly, Crystal;Williams, Kelly L.;Fifita, Jennifer A.;Maragakis, Nicholas J.;Nicholson, Garth A.;King, Oliver D.;Reed, Robin;Crabtree, Gerald R.;Blair, Ian P.;Glass, Jonathan D.;Gitler, Aaron D.
通讯作者：
Gitler, Aaron D.
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
DOI：
10.1093/brain/awu120
发表时间：
2014-07
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Cooper-Knock J;Walsh MJ;Higginbottom A;Robin Highley J;Dickman MJ;Edbauer D;Ince PG;Wharton SB;Wilson SA;Kirby J;Hautbergue GM;Shaw PJ
通讯作者：
Shaw PJ