Developmental regulation of tau splicing is disrupted in stem cell-derived neurons from frontotemporal dementia patients with the 10 + 16 splice-site mutation in MAPT.
Developmental regulation of tau splicing is disrupted in stem cell-derived neurons from frontotemporal dementia patients with the 10 + 16 splice-site mutation in MAPT.
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DOI：
10.1093/hmg/ddv246
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发表时间：
2015-09-15
影响因子：
3.5
通讯作者：
Wray S
中科院分区：
文献类型：
--
作者：
Sposito T;Preza E;Mahoney CJ;Setó-Salvia N;Ryan NS;Morris HR;Arber C;Devine MJ;Houlden H;Warner TT;Bushell TJ;Zagnoni M;Kunath T;Livesey FJ;Fox NC;Rossor MN;Hardy J;Wray S
tau基因的选择性剪接（MAPT）在成人中枢神经系统（CNS）中产生六种蛋白质同种型。Tau剪接在疾病中受到发育调节和失调。改变tau剪接的MAPT突变导致额颞叶痴呆（FTD）伴tau病理，为改变的tau剪接和疾病之间的因果关系提供了证据。诱导多能干细胞（iPSC）衍生神经元的使用彻底改变了我们体外模拟神经疾病的方式。然而，由于大多数tau突变位于选择性剪接外显子10内或周围，因此iPSC神经元适当地剪接tau以用作疾病模型是重要的。为了解决这个问题，我们分析了来自对照患者和具有MAPT中10 + 16内含子突变的FTD患者的iPSC衍生的皮质神经元中tau的表达和剪接。我们发现，控制神经元只表达胎儿tau亚型（0N3R），即使在体外延长100天的时间点。来自携带MAPT 10 + 16突变的FTD患者的神经元同时表达0N3R和0N4R tau亚型，表明该突变超越了我们体外模型中包含外显子10的发育调控。此外，在体外365天的延长时间点，我们观察到tau剪接的转换，包括六种tau亚型，如在成人CNS中所见。我们的研究结果证明了神经元成熟度在体外建模中的重要性，并提供了一个系统，这将是重要的了解改变tau蛋白剪接的功能后果。
The alternative splicing of the tau gene, MAPT, generates six protein isoforms in the adult human central nervous system (CNS). Tau splicing is developmentally regulated and dysregulated in disease. Mutations in MAPT that alter tau splicing cause frontotemporal dementia (FTD) with tau pathology, providing evidence for a causal link between altered tau splicing and disease. The use of induced pluripotent stem cell (iPSC)-derived neurons has revolutionized the way we model neurological disease in vitro. However, as most tau mutations are located within or around the alternatively spliced exon 10, it is important that iPSC–neurons splice tau appropriately in order to be used as disease models. To address this issue, we analyzed the expression and splicing of tau in iPSC-derived cortical neurons from control patients and FTD patients with the 10 + 16 intronic mutation in MAPT. We show that control neurons only express the fetal tau isoform (0N3R), even at extended time points of 100 days in vitro. Neurons from FTD patients with the 10 + 16 mutation in MAPT express both 0N3R and 0N4R tau isoforms, demonstrating that this mutation overrides the developmental regulation of exon 10 inclusion in our in vitro model. Further, at extended time points of 365 days in vitro, we observe a switch in tau splicing to include six tau isoforms as seen in the adult human CNS. Our results demonstrate the importance of neuronal maturity for use in in vitro modeling and provide a system that will be important for understanding the functional consequences of altered tau splicing.