Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI-CONICET), C1428ADN Buenos Aires, Argentina.
Instituto de Biología y Medicina Experimental (IBYME-CONICET), C1428ADN Buenos Aires, Argentina.
Brain. 2021 Sep 4;144(8):2302-2309. doi: 10.1093/brain/awab130.
Tauopathies are neurodegenerative diseases caused by the abnormal metabolism of the microtubule associated protein tau (MAPT), which is highly expressed in neurons and critically involved in microtubule dynamics. In the adult human brain, the alternative splicing of exon 10 in MAPT pre-mRNA produces equal amounts of protein isoforms with either three (3R) or four (4R) microtubule binding domains. Imbalance in the 3R:4R tau ratio is associated with primary tauopathies that develop atypical parkinsonism, such as progressive supranuclear palsy and corticobasal degeneration. Yet, the development of effective therapies for those pathologies is an unmet goal. Here we report motor coordination impairments in the htau mouse model of tauopathy which harbour abnormal 3R:4R tau isoforms content, and in contrast to TauKO mice, are unresponsive to l-DOPA. Preclinical-PET imaging, array tomography and electrophysiological analyses indicated the dorsal striatum as the candidate structure mediating such phenotypes. Indeed, local modulation of tau isoforms by RNA trans-splicing in the striata of adult htau mice, prevented motor coordination deficits and restored basal neuronal firing. Together, these results suggest that abnormal striatal tau isoform content might lead to parkinsonian-like phenotypes and demonstrate a proof of concept that modulation of tau mis-splicing is a plausible disease-modifying therapy for some primary tauopathies.
tau 病是由微管相关蛋白 tau（MAPT）的异常代谢引起的神经退行性疾病，MAPT 在神经元中高度表达，并且对微管动力学具有重要作用。在成人脑中，MAPT 前体 mRNA 中外显子 10 的选择性剪接产生具有三个（3R）或四个（4R）微管结合结构域的等量蛋白异构体。3R：4R tau 比率失衡与原发性 tau 病有关，这些疾病会发展出非典型帕金森病，如进行性核上性麻痹和皮质基底节变性。然而，开发针对这些病理的有效治疗方法仍是一个未满足的目标。在这里，我们报告了 tau 病的 htau 小鼠模型中运动协调障碍，该模型具有异常的 3R：4R tau 异构体含量，与 TauKO 小鼠不同，对 l-DOPA 无反应。临床前-PET 成像、阵列断层扫描和电生理分析表明，背侧纹状体是介导这种表型的候选结构。事实上，通过在成年 htau 小鼠纹状体中的 RNA 反式剪接来调节 tau 异构体，可以防止运动协调缺陷并恢复基底神经元放电。总之，这些结果表明，异常纹状体 tau 异构体含量可能导致类似帕金森病的表型，并证明了调节 tau 错剪接是一些原发性 tau 病可行的疾病修饰治疗方法的概念验证。
