Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK.
Division of Neuroscience, Biomedical Sciences Research Centre "Alexander Fleming", Vari 16672, Greece.
Neurobiol Dis. 2017 Sep;105:74-83. doi: 10.1016/j.nbd.2017.05.003. Epub 2017 May 11.
Tau exists as six closely related protein isoforms in the adult human brain. These are generated from alternative splicing of a single mRNA transcript and they differ in the absence or presence of two N-terminal and three or four microtubule binding domains. Typically all six isoforms have been considered functionally similar. However, their differential involvement in particular tauopathies raises the possibility that there may be isoform-specific differences in physiological function and pathological role. To explore this, we have compared the phenotypes induced by the 0N3R and 0N4R isoforms in Drosophila. Expression of the 3R isoform causes more profound axonal transport defects and locomotor impairments, culminating in a shorter lifespan than the 4R isoform. In contrast, the 4R isoform leads to greater neurodegeneration and impairments in learning and memory. Furthermore, the phosphorylation patterns of the two isoforms are distinct, as is their ability to induce oxidative stress. These differences are not consequent to different expression levels and are suggestive of bona fide physiological differences in isoform biology and pathological potential. They may therefore explain isoform-specific mechanisms of tau-toxicity and the differential susceptibility of brain regions to different tauopathies.
在成人脑中，Tau 以六种密切相关的蛋白异构体存在。这些异构体通过单个 mRNA 转录本的选择性剪接产生，它们在缺乏或存在两个 N 端和三个或四个微管结合结构域方面存在差异。通常，所有六种异构体在功能上被认为是相似的。然而，它们在特定 tau 病中的差异参与提出了这样一种可能性，即生理功能和病理作用可能存在异构体特异性差异。为了探索这一点，我们比较了果蝇中 0N3R 和 0N4R 异构体诱导的表型。3R 异构体的表达导致更严重的轴突运输缺陷和运动障碍，最终比 4R 异构体寿命更短。相比之下，4R 异构体导致更大的神经退行性变和学习记忆障碍。此外，两种异构体的磷酸化模式不同，诱导氧化应激的能力也不同。这些差异不是由于表达水平的不同，而是暗示了异构体生物学和病理潜力方面的真正生理差异。因此，它们可能解释了 tau 毒性的异构体特异性机制以及不同 tau 病对不同脑区的不同易感性。
