Laboratory of Biology, BIO@SNS, Scuola Normale Superiore, Pisa, Italy.
Unit of Histology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
J Mol Biol. 2019 Feb 15;431(4):873-884. doi: 10.1016/j.jmb.2019.01.023. Epub 2019 Jan 18.
Tau displacement from microtubules is the first step in the onset of tauopathies and is followed by toxic protein aggregation. However, other non-canonical functions of Tau might have a role in these pathologies. Here, we demonstrate that a small amount of Tau localizes in the nuclear compartment and accumulates in both the soluble and chromatin-bound fractions. We show that favoring Tau nuclear translocation and accumulation, by Tau overexpression or detachment from MTs, increases the expression of VGluT1, a disease-relevant gene directly involved in glutamatergic synaptic transmission. Remarkably, the P301L mutation, related to frontotemporal dementia FTDP-17, impairs this mechanism leading to a loss of function. Altogether, our results provide the demonstration of a direct physiological role of Tau on gene expression. Alterations of this mechanism may be at the basis of the onset of neurodegeneration.
tau 蛋白从微管上脱离是 tau 病发生的第一步，随后会发生毒性蛋白聚集。然而，tau 蛋白的其他非典型功能可能在这些病变中发挥作用。在这里，我们证明了少量的 tau 蛋白定位于核区，并在可溶部分和染色质结合部分积累。我们发现，tau 蛋白的过表达或与微管的脱离，有利于 tau 蛋白向核内易位和积累，从而增加了 VGluT1 的表达，该基因与谷氨酸能突触传递直接相关，是一种与疾病相关的基因。值得注意的是，与额颞叶痴呆 FTDP-17 相关的 P301L 突变破坏了这一机制，导致功能丧失。总之，我们的研究结果提供了 tau 蛋白对基因表达的直接生理作用的证据。这种机制的改变可能是神经退行性变发生的基础。
