Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas (INGEBI-CONICET), Buenos Aires, Argentina.
Universidad de Buenos Aires, Facultad de Medicina, Departamento de Fisiología, Buenos Aires, Argentina; Instituto de Fisiología y Biofísica "Bernardo Houssay" (IFIBIO-Houssay-CONICET), Buenos Aires, Argentina.
Cell Rep. 2018 Apr 17;23(3):709-715. doi: 10.1016/j.celrep.2018.03.079.
The microtubule-associated protein tau regulates myriad neuronal functions, such as microtubule dynamics, axonal transport and neurite outgrowth. Tauopathies are neurodegenerative disorders characterized by the abnormal metabolism of tau, which accumulates as insoluble neuronal deposits. The adult human brain contains equal amounts of tau isoforms with three (3R) or four (4R) repeats of microtubule-binding domains, derived from the alternative splicing of exon 10 (E10) in the tau transcript. Several tauopathies are associated with imbalances of tau isoforms, due to splicing deficits. Here, we used a trans-splicing strategy to shift the inclusion of E10 in a mouse model of tauopathy that produces abnormal excess of 3R tau. Modulating the 3R/4R ratio in the prefrontal cortex led to a significant reduction of pathological tau accumulation concomitant with improvement of neuronal firing and reduction of cognitive impairments. Our results suggest promising potential for the use of RNA reprogramming in human neurodegenerative diseases.
微管相关蛋白 tau 调节着众多神经元功能，如微管动力学、轴突运输和神经突生长。tau 病是神经退行性疾病的特征，其 tau 异常代谢，积累为不溶性神经元沉积物。成人脑中含有等量的具有三个（3R）或四个（4R）微管结合结构域重复的 tau 异构体，这些异构体来自 tau 转录物外显子 10（E10）的选择性剪接。由于剪接缺陷，几种 tau 病与 tau 异构体的失衡有关。在这里，我们使用反式剪接策略来改变 tau 病小鼠模型中 E10 的包含，该模型产生异常过多的 3R tau。调节前额叶皮层中的 3R/4R 比值可显著减少病理性 tau 的积累，同时改善神经元放电并减少认知障碍。我们的结果表明，在人类神经退行性疾病中使用 RNA 重编程具有很大的潜力。
