An AGS-associated mutation in ADAR1 catalytic domain results in early-onset and MDA5-dependent encephalopathy with IFN pathway activation in the brain.
An AGS-associated mutation in ADAR1 catalytic domain results in early-onset and MDA5-dependent encephalopathy with IFN pathway activation in the brain.
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DOI：
10.1186/s12974-022-02646-0
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发表时间：
2022-12-01
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
Aicardi-Goutières综合征（AGS）是一种严重的神经退行性疾病，临床特征为早发性脑病和进行性智力和运动控制能力丧失。已发现7个蛋白质编码基因的基因突变与AGS相关。然而，这些突变在早发性神经发病机制中的致病作用尚未在动物模型中得到证实，AGS神经变性的机制仍然不明确。通过CRISPR/Cas-9技术，我们建立了一种突变小鼠模型，其中在AGS患者中发现的ADAR 1编码基因（阿达尔）位点的遗传突变被引入小鼠基因组。使用育种策略制备携带编码ADAR 1和MDA-5的双基因突变的小鼠模型。表型、基因表达、RNA测序、先天免疫途径激活和病理学研究（包括RNA原位杂交（ISH）和免疫组织化学）用于表征小鼠模型，以确定潜在的疾病机制。我们建立了一个携带ADAR 1催化结构域突变的小鼠模型，即AGS患者中发现的D1113 H突变。利用该小鼠模型，我们证明了该突变对AGS中早发性脑损伤的致病作用，并确定了神经发病机制的信号通路。首先，这种突变改变了神经转录物中的RNA编辑谱，并导致大脑中强烈的IFN刺激基因（ISG）表达。通过ISH，突变小鼠的大脑显示出不寻常的、多灶性的ISGs表达增加，这是细胞类型依赖性的。在突变小鼠中观察到早发性星形细胞增多和小胶质细胞增多以及深白色物质区的晚期钙化。在阿达尔D1113 H突变小鼠中，通过删除胞质RNA受体MDA-5阻断RNA传感，完全防止了脑ISG激活和神经胶质反应。在小鼠脑中，ADAR 1催化结构域中的阿达尔D1113 H突变导致早发性和MDA 5依赖性脑病，并伴有IFN途径激活。在线版本包含补充材料，可通过10.1186/s12974-022-02646-0获得。
Aicardi–Goutières syndrome (AGS) is a severe neurodegenerative disease with clinical features of early-onset encephalopathy and progressive loss of intellectual abilities and motor control. Gene mutations in seven protein-coding genes have been found to be associated with AGS. However, the causative role of these mutations in the early-onset neuropathogenesis has not been demonstrated in animal models, and the mechanism of neurodegeneration of AGS remains ambiguous. Via CRISPR/Cas-9 technology, we established a mutant mouse model in which a genetic mutation found in AGS patients at the ADAR1 coding gene (Adar) loci was introduced into the mouse genome. A mouse model carrying double gene mutations encoding ADAR1 and MDA-5 was prepared using a breeding strategy. Phenotype, gene expression, RNA sequencing, innate immune pathway activation, and pathologic studies including RNA in situ hybridization (ISH) and immunohistochemistry were used for characterization of the mouse models to determine potential disease mechanisms. We established a mouse model bearing a mutation in the catalytic domain of ADAR1, the D1113H mutation found in AGS patients. With this mouse model, we demonstrated a causative role of this mutation for the early-onset brain injuries in AGS and determined the signaling pathway underlying the neuropathogenesis. First, this mutation altered the RNA editing profile in neural transcripts and led to robust IFN-stimulated gene (ISG) expression in the brain. By ISH, the brains of mutant mice showed an unusual, multifocal increased expression of ISGs that was cell-type dependent. Early-onset astrocytosis and microgliosis and later stage calcification in the deep white matter areas were observed in the mutant mice. Brain ISG activation and neuroglial reaction were completely prevented in the Adar D1113H mutant mice by blocking RNA sensing through deletion of the cytosolic RNA receptor MDA-5. The Adar D1113H mutation in the ADAR1 catalytic domain results in early-onset and MDA5-dependent encephalopathy with IFN pathway activation in the mouse brain. The online version contains supplementary material available at 10.1186/s12974-022-02646-0.
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DOI：
10.1038/s41577-021-00633-9
发表时间：
2022-08
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Crow YJ;Stetson DB
通讯作者：
Stetson DB
影响因子：
4.5
作者：
Kim JI;Nakahama T;Yamasaki R;Costa Cruz PH;Vongpipatana T;Inoue M;Kanou N;Xing Y;Todo H;Shibuya T;Kato Y;Kawahara Y
通讯作者：
Kawahara Y
影响因子：
4.4
作者：
Guo X;Liu S;Yan R;Nguyen V;Zenati M;Billiar TR;Wang Q
通讯作者：
Wang Q
影响因子：
8.8
作者：
Mannion NM;Greenwood SM;Young R;Cox S;Brindle J;Read D;Nellåker C;Vesely C;Ponting CP;McLaughlin PJ;Jantsch MF;Dorin J;Adams IR;Scadden AD;Ohman M;Keegan LP;O'Connell MA
通讯作者：
O'Connell MA
影响因子：
2
作者：
Crow, Yanick J.;Chase, Diana S.;Schmidt, Johanna Lowenstein;Szynkiewicz, Marcin;Forte, Gabriella M. A.;Gornall, Hannah L.;Oojageer, Anthony;Anderson, Beverley;Pizzino, Amy;Helman, Guy;Abdel-Hamid, Mohamed S.;Abdel-Salam, Ghada M.;Ackroyd, Sam;Aeby, Alec;Agosta, Guillermo;Albin, Catherine;Allon-Shalev, Stavit;Arellano, Montse;Ariaudo, Giada;Aswani, Vijay;Babul-Hirji, Riyana;Baildam, Eileen M.;Bahi-Buisson, Nadia;Bailey, Kathryn M.;Barnerias, Christine;Barth, Magalie;Battini, Roberta;Beresford, Michael W.;Bernard, Genevieve;Bianchi, Marika;de Villemeur, Thierry Billette;Blair, Edward M.;Bloom, Miriam;Burlina, Alberto B.;Carpanelli, Maria Luisa;Carvalho, Daniel R.;Castro-Gago, Manuel;Cavallini, Anna;Cereda, Cristina;Chandler, Kate E.;Chitayat, David A.;Collins, Abigail E.;Sierra Corcoles, Concepcion;Cordeiro, Nuno J. V.;Crichiutti, Giovanni;Dabydeen, Lyvia;Dale, Russell C.;D'Arrigo, Stefano;De Goede, Christian G. E. L.;De Laet, Corinne;De Waele, Liesbeth M. H.;Denzler, Ines;Desguerre, Isabelle;Devriendt, Koenraad;Di Rocco, Maja;Fahey, Michael C.;Fazzi, Elisa;Ferrie, Colin D.;Figueiredo, Antonio;Gener, Blanca;Goizet, Cyril;Gowrinathan, Nirmala R.;Gowrishankar, Kalpana;Hanrahan, Donncha;Isidor, Bertrand;Kara, Lent;Khan, Nasaim;King, Mary D.;Kirk, Edwin P.;Kumar, Ram;Lagae, Lieven;Landrieu, Pierre;Lauffer, Heinz;Laugel, Vincent;La Piana, Roberta;Lim, Ming J.;Lin, Jean-Pierre S. -M.;Linnankivi, Tarja;Mackay, Mark T.;Marom, Daphna R.;Lourenco, Charles Marques;McKee, Shane A.;Moroni, Isabella;Morton, Jenny E. V.;Moutard, Marie-Laure;Murray, Kevin;Nabbout, Rima;Nampoothiri, Sheela;Nunez-Enamorado, Noemi;Oades, Patrick J.;Olivieri, Ivana;Ostergaard, John R.;Perez-Duenas, Belen;Prendiville, Julie S.;Ramesh, Venkateswaran;Rasmussen, Magnhild;Regal, Luc;Ricci, Federica;Rio, Marlene;Rodriguez, Diana;Roubertie, Agathe;Salvatici, Elisabetta;Segers, Karin A.;Sinha, Gyanranjan P.;Soler, Doriette;Spiegel, Ronen;Stoedberg, Tommy I.;Straussberg, Rachel;Swoboda, Kathryn J.;Suri, Mohnish;Tacke, Uta;Tan, Tiong Y.;Naude, Johann te Water;Teik, Keng Wee;Thomas, Maya Mary;Till, Marianne;Tonduti, Davide;Valente, Enza Maria;Van Coster, Rudy Noel;van der Knaap, Marjo S.;Vassallo, Grace;Vijzelaar, Raymon;Vogt, Julie;Wallace, Geoffrey B.;Wassmer, Evangeline;Webb, Hannah J.;Whitehouse, William P.;Whitney, Robyn N.;Zaki, Maha S.;Zuberi, Sameer M.;Livingston, John H.;Rozenberg, Flore;Lebon, Pierre;Vanderver, Adeline;Orcesi, Simona;Rice, Gillian I.
通讯作者：
Rice, Gillian I.