Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing.
Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing.
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DOI：
10.1093/hmg/ddt108
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发表时间：
2013-07-01
影响因子：
3.5
通讯作者：
Gallo JM
中科院分区：
文献类型：
--
作者：
Avale ME;Rodríguez-Martín T;Gallo JM
tau蛋白的异常代谢是包括阿尔茨海默病在内的许多痴呆症的发病机制的核心。tau前体mRNA中外显子10的异常选择性剪接导致tau亚型的不平衡，是遗传性tau蛋白病FTDP-17的分子原因之一。我们先前在异源系统中表明，tau mRNA中包含的外显子10可以通过剪接体介导的RNA反式剪接（SMaRT）进行调节。在这里，我们评估了潜在的反式剪接RNA重编程，以纠正tau错误剪接的小鼠模型中分化的神经元中的tau错误剪接，htau转基因小鼠系，表达人类MAPT基因在空小鼠Mapt背景。使用慢病毒载体将设计用于增加外显子10包含的反式剪接分子递送至神经元。我们证明了在培养的神经元转导后或在体内将病毒载体直接递送和长期表达到htau小鼠的脑中后，在RNA水平上对tau转录物进行重编程。Tau RNA反式剪接导致成熟Tau mRNA中包含的外显子10增加。重要的是，我们还表明，反式剪接产物被翻译成全长嵌合tau蛋白。这些结果验证了SMaRT纠正tau错误剪接的潜力，并为其在与异常RNA加工相关的神经退行性疾病中的治疗应用提供了框架。
Abnormal metabolism of the tau protein is central to the pathogenesis of a number of dementias, including Alzheimer's disease. Aberrant alternative splicing of exon 10 in the tau pre-mRNA resulting in an imbalance of tau isoforms is one of the molecular causes of the inherited tauopathy, FTDP-17. We showed previously in heterologous systems that exon 10 inclusion in tau mRNA could be modulated by spliceosome-mediated RNA trans-splicing (SMaRT). Here, we evaluated the potential of trans-splicing RNA reprogramming to correct tau mis-splicing in differentiated neurons in a mouse model of tau mis-splicing, the htau transgenic mouse line, expressing the human MAPT gene in a null mouse Mapt background. Trans-splicing molecules designed to increase exon 10 inclusion were delivered to neurons using lentiviral vectors. We demonstrate reprogramming of tau transcripts at the RNA level after transduction of cultured neurons or after direct delivery and long-term expression of viral vectors into the brain of htau mice in vivo. Tau RNA trans-splicing resulted in an increase in exon 10 inclusion in the mature tau mRNA. Importantly, we also show that the trans-spliced product is translated into a full-length chimeric tau protein. These results validate the potential of SMaRT to correct tau mis-splicing and provide a framework for its therapeutic application to neurodegenerative conditions linked to aberrant RNA processing.
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影响因子：
5.3
作者：
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通讯作者：
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影响因子：
16.2
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DOI：
10.1073/pnas.0503150102
发表时间：
2005-10-25
影响因子：
11.1
作者：
Rodriguez-Martin, T;Garcia-Blanco, MA;Gallo, JM
通讯作者：
Gallo, JM