Modeling of TREX1-Dependent Autoimmune Disease using Human Stem Cells Highlights L1 Accumulation as a Source of Neuroinflammation.
Modeling of TREX1-Dependent Autoimmune Disease using Human Stem Cells Highlights L1 Accumulation as a Source of Neuroinflammation.
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DOI：
10.1016/j.stem.2017.07.009
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发表时间：
2017-09-07
期刊：
影响因子：
23.9
通讯作者：
Muotri AR
中科院分区：
文献类型：
--
作者：
Thomas CA;Tejwani L;Trujillo CA;Negraes PD;Herai RH;Mesci P;Macia A;Crow YJ;Muotri AR
三素修复核酸外切酶I（TREX 1）是一种抗病毒酶，其切割胞质溶胶中的核酸，防止积聚和随后的I型干扰素相关的炎症反应。自身免疫性疾病，包括Aicardi-Goutières综合征（AGS）和系统性红斑狼疮，可在TREX 1功能受损时出现。AGS是一种神经炎症性疾病，伴有严重和持续的智力和身体问题。在这里，我们生成了一个人类AGS模型，该模型使用缺乏TREX 1的多能干细胞重现疾病相关表型。我们在TREX 1缺陷的神经细胞中观察到丰富的染色体外DNA，其中内源性长散布元件-1逆转录转座子是主要来源。TREX 1缺陷的神经元也表现出增加的凋亡，并形成三维皮质类器官的大小减少。TREX 1缺陷型星形胶质细胞通过增加I型干扰素分泌进一步促进观察到的神经毒性。在该模型中，逆转录酶抑制剂挽救了AGS神经元和类器官的神经毒性，突出了它们在AGS和相关疾病的治疗方案中的潜在效用。托马斯，Tejwani等人使用人类多能干细胞来剖析神经元和神经胶质对神经炎性疾病Aicardi-Goutières综合征（AGS）的贡献。他们发现突变细胞积累逆转录病毒样染色体外核酸，引发神经毒性反应，并表明抗逆转录病毒药物可能为这种疾病提供治疗。
Three-prime repair exonuclease I (TREX1) is an anti-viral enzyme that cleaves nucleic acids in the cytosol, preventing accumulation and a subsequent type-I interferon-associated inflammatory response. Autoimmune diseases, including Aicardi-Goutières syndrome (AGS) and systemic lupus erythematosus, can arise when TREX1 function is compromised. AGS is a neuroinflammatory disorder with severe and persistent intellectual and physical problems. Here, we generated a human AGS model that recapitulates disease-relevant phenotypes using pluripotent stem cells lacking TREX1. We observed abundant extrachromosomal DNA in TREX1-deficient neural cells, of which endogenous Long Interspersed Element-1 retrotransposons were a major source. TREX1-deficient neurons also exhibited increased apoptosis and formed three-dimensional cortical organoids of reduced size. TREX1-deficient astrocytes further contributed to the observed neurotoxicity through increased type-I interferon secretion. In this model, reverse transcriptase inhibitors rescued the neurotoxicity of AGS neurons and organoids, highlighting their potential utility in therapeutic regimens for AGS and related disorders. Thomas, Tejwani et al. used human pluripotent stem cells to dissect the contribution of neurons and glia to the neuroinflammatory disorder Aicardi-Goutières syndrome (AGS). They found that mutant cells accumulate retroviral-like extrachromosomal nucleic acids that trigger a neurotoxic response, and suggest that anti-retrovirals could potentially provide therapy for this disease.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
32.4
作者：
Gall A;Treuting P;Elkon KB;Loo YM;Gale M Jr;Barber GN;Stetson DB
通讯作者：
Stetson DB
影响因子：
9.8
作者：
Brouha, B;Meischl, C;Kazazian, HH
通讯作者：
Kazazian, HH
对非综合自闭症进行建模以及TRPC6破坏在人神经元中的影响。
影响因子：
11
作者：
Griesi-Oliveira, K.;Acab, A.;Gupta, A. R.;Sunaga, D. Y.;Chailangkarn, T.;Nicol, X.;Nunez, Y.;Walker, M. F.;Murdoch, J. D.;Sanders, S. J.;Fernandez, T. V.;Ji, W.;Lifton, R. P.;Vadasz, E.;Dietrich, A.;Pradhan, D.;Song, H.;Ming, G-I;Gu, X.;Haddad, G.;Marchetto, M. C. N.;Spitzer, N.;Passos-Bueno, M. R.;State, M. W.;Muotri, A. R.
通讯作者：
Muotri, A. R.
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.