Molecular and Cellular Neurobiotechnology, Institute for Bioengineering of Catalonia (IBEC), Scientific Park of Barcelona, The Barcelona Institute for Science and Technology (BIST), 08028 Barcelona, Spain.
Department of Cell Biology, Physiology and Immunology, University of Barcelona, 08028 Barcelona, Spain.
Int J Mol Sci. 2021 May 20;22(10):5370. doi: 10.3390/ijms22105370.
Tau protein is largely responsible for tauopathies, including Alzheimer's disease (AD), where it accumulates in the brain as insoluble aggregates. Tau mRNA is regulated by alternative splicing, and inclusion or exclusion of exon 10 gives rise to the 3R and 4R isoforms respectively, whose balance is physiologically regulated. In this sense, one of the several factors that regulate alternative splicing of tau is GSK3β, whose activity is inhibited by the cellular prion protein (PrP), which has different physiological functions in neuroprotection and neuronal differentiation. Moreover, a relationship between PrP and tau expression levels has been reported during AD evolution. For this reason, in this study we aimed to analyze the role of PrP and the implication of GSK3β in the regulation of tau exon 10 alternative splicing. We used AD human samples and mouse models of PrP ablation and tau overexpression. In addition, we used primary neuronal cultures to develop functional studies. Our results revealed a paralleled association between PrP expression and tau 4R isoforms in all models analyzed. In this sense, reduction or ablation of PrP levels induces an increase in tau 3R/4R balance. More relevantly, our data points to GSK3β activity downstream from PrP in this phenomenon. Our results indicate that PrP plays a role in tau exon 10 inclusion through the inhibitory capacity of GSK3β.
tau 蛋白在很大程度上负责包括阿尔茨海默病（AD）在内的 tau 病，在 AD 中，tau 蛋白在大脑中积累为不溶性聚集体。tau mRNA 通过选择性剪接进行调节，外显子 10 的包含或排除分别产生 3R 和 4R 异构体，其平衡受生理调节。在这个意义上，调节 tau 选择性剪接的几个因素之一是 GSK3β，其活性被细胞朊病毒蛋白（PrP）抑制，PrP 在神经保护和神经元分化中有不同的生理功能。此外，在 AD 演变过程中已经报道了 PrP 和 tau 表达水平之间的关系。出于这个原因，在这项研究中，我们旨在分析 PrP 的作用以及 GSK3β 在 tau 外显子 10 选择性剪接调节中的作用。我们使用 AD 人类样本和 PrP 缺失和 tau 过表达的小鼠模型。此外，我们使用原代神经元培养物进行功能研究。我们的结果揭示了所有分析模型中 PrP 表达与 tau 4R 异构体之间的平行关联。在这个意义上，PrP 水平的降低或缺失会导致 tau 3R/4R 平衡增加。更重要的是，我们的数据表明 GSK3β 活性是 PrP 下游在这种现象中的作用。我们的结果表明，PrP 通过 GSK3β 的抑制能力在 tau 外显子 10 的包含中发挥作用。
