Granulin loss of function in human mature brain organoids implicates astrocytes in TDP-43 pathology.
Granulin loss of function in human mature brain organoids implicates astrocytes in TDP-43 pathology.
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DOI：
10.1016/j.stemcr.2023.01.012
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发表时间：
2023-03-14
影响因子：
5.9
通讯作者：
Ullian, Erik M.
中科院分区：
文献类型：
--
作者：
de Majo, Martina;Koontz, Mark;Marsan, Elise;Salinas, Nir;Ramsey, Arren;Kuo, Yien-Ming;Seo, Kyounghee;Li, Huinan;Drager, Nina;Leng, Kun;Gonzales, Santiago L.;Kurnellas, Michael;Miyaoka, Yuichiro;Klim, Joseph R.;Kampmann, Martin;Ward, Michael E.;Huang, Eric J.;Ullian, Erik M.
在肌萎缩侧索硬化症（ALS）和额颞叶痴呆症（FTD）患者的死后组织中发现了TAR-DNA结合蛋白43（TDP-43）的功能丧失（LoF）和错误定位，以及TDP-43阳性和过度磷酸化的内含物，包括那些携带颗粒蛋白前体基因（GRN）LoF变体的患者。在体内和体外建模TDP-43病理学一直具有挑战性。我们提出了一个三维诱导多能干细胞（iPSC）衍生的范例-成熟的脑类器官（mbaroid）-由皮质样星形胶质细胞（iA）和神经元组成。当缺乏GRN时，mbOrgs自发地重现TDP-43错误定位、过度磷酸化和LoF表型。在mbOrgs中混合和匹配基因型表明，GRN−/− iA是TDP-43病理学的驱动因素。最后，我们通过添加外源性颗粒蛋白前体挽救了TDP-43 LoF，证明了TDP-43 LoF与颗粒蛋白前体表达之间的联系。总之，我们提出了一个iPSC衍生的平台，该平台显示了人类TDP-43蛋白质病的显著特征，并为TDP-43病理学的机制建模和FTD和ALS的患者定制治疗筛选提供了工具。由成熟星形胶质细胞和神经元制成的GRN−/− mbOrgs显示TDP-43病理学特征GRN−/−星形胶质细胞是必要的，并且足以在mborgan中进行STMN 2错误剪接STMN 2错误剪接被拯救，将颗粒蛋白前体添加到神经元和星形胶质细胞共培养物中。提出了一种新的3D iPSC衍生模型来研究神经退行性疾病，如ALS和FTD。当缺乏GRN表达时，这些培养物呈现出在体外几乎从未观察到的ALS和FTD相关病理学特征。这些表型显示主要由患病的星形胶质细胞驱动，并且可以通过颗粒蛋白前体补充来挽救。
Loss of function (LoF) of TAR-DNA binding protein 43 (TDP-43) and mis-localization, together with TDP-43-positive and hyperphosphorylated inclusions, are found in post-mortem tissue of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those carrying LoF variants in the progranulin gene (GRN). Modeling TDP-43 pathology has been challenging in vivo and in vitro. We present a three-dimensional induced pluripotent stem cell (iPSC)-derived paradigm—mature brain organoids (mbOrg)—composed of cortical-like-astrocytes (iA) and neurons. When devoid of GRN, mbOrgs spontaneously recapitulate TDP-43 mis-localization, hyperphosphorylation, and LoF phenotypes. Mixing and matching genotypes in mbOrgs showed that GRN−/− iA are drivers for TDP-43 pathology. Finally, we rescued TDP-43 LoF by adding exogenous progranulin, demonstrating a link between TDP-43 LoF and progranulin expression. In conclusion, we present an iPSC-derived platform that shows striking features of human TDP-43 proteinopathy and provides a tool for the mechanistic modeling of TDP-43 pathology and patient-tailored therapeutic screening for FTD and ALS. GRN−/− mbOrgs made of mature astrocytes and neurons show traits of TDP-43 pathology GRN−/− astrocytes are necessary and sufficient for STMN2 mis-splicing in mbOrg STMN2 mis-splicing is rescued, adding progranulin to neuron and astrocyte co-cultures In this article, de Majo et al. present a novel 3D iPSC-derived model to study neurodegenerative disorders such as ALS and FTD. When devoid of GRN expression, these cultures present features of ALS- and FTD-associated pathology hardly ever observed in vitro. These phenotypes are shown to be primarily driven by diseased astrocytes and can be rescued by pro-granulin supplementation.
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影响因子：
64.8
作者：
Cruts, Marc;Gijselinck, Ilse;Van Broeckhoven, Christine
通讯作者：
Van Broeckhoven, Christine
影响因子：
8.8
作者：
Almeida S;Zhang Z;Coppola G;Mao W;Futai K;Karydas A;Geschwind MD;Tartaglia MC;Gao F;Gianni D;Sena-Esteves M;Geschwind DH;Miller BL;Farese RV Jr;Gao FB
通讯作者：
Gao FB
影响因子：
17.1
作者：
通讯作者：
--
影响因子：
6
作者：
Desai, Maya K.;Mastrangelo, Michael A.;Bowers, William J.
通讯作者：
Bowers, William J.
系统的三维共培养迅速概括了人类神经元与星形胶质细胞之间的相互作用。
影响因子：
5.9
作者：
Krencik R;Seo K;van Asperen JV;Basu N;Cvetkovic C;Barlas S;Chen R;Ludwig C;Wang C;Ward ME;Gan L;Horner PJ;Rowitch DH;Ullian EM
通讯作者：
Ullian EM