Department of Molecular and Cellular Mechanisms of Neurodegeneration, Paul Flechsig Institute of Brain Research, University of Leipzig, Leipzig, Germany.
PLoS One. 2011 Jan 18;6(1):e14530. doi: 10.1371/journal.pone.0014530.
Abnormal phosphorylation and aggregation of tau protein are hallmarks of a variety of neurological disorders, including Alzheimer's disease (AD). Increased tau phosphorylation is assumed to represent an early event in pathogenesis and a pivotal aspect for aggregation and formation of neurofibrillary tangles. However, the regulation of tau phosphorylation in vivo and the causes for its increased stage of phosphorylation in AD are still not well understood, a fact that is primarily based on the lack of adequate animal models. Recently we described the reversible formation of highly phosphorylated tau protein in hibernating European ground squirrels. Hence, mammalian hibernation represents a model system very well suited to study molecular mechanisms of both tau phosphorylation and dephosphorylation under in vivo physiological conditions. Here, we analysed the extent and kinetics of hibernation-state dependent tau phosphorylation in various brain regions of three species of hibernating mammals: arctic ground squirrels, Syrian hamsters and black bears. Overall, tau protein was highly phosphorylated in torpor states and phosphorylation levels decreased after arousal in all species. Differences between brain regions, hibernation-states and phosphosites were observed with respect to degree and kinetics of tau phosphorylation. Furthermore, we tested the phosphate net turnover of tau protein to analyse potential alterations in kinase and/or phosphatase activities during hibernation. Our results demonstrate that the hibernation-state dependent phosphorylation of tau protein is specifically regulated but involves, in addition, passive, temperature driven regulatory mechanisms. By determining the activity-state profile for key enzymes of tau phosphorylation we could identify kinases potentially involved in the differentially regulated, reversible tau phosphorylation that occurs during hibernation. We show that in black bears hibernation is associated with conformational changes of highly phosphorylated tau protein that are typically related to neuropathological alterations. The particular hibernation characteristics of black bears with a continuous torpor period and an only slightly decreased body temperature, therefore, potentially reflects the limitations of this adaptive reaction pattern and, thus, might indicate a transitional state of a physiological process.
异常的 tau 蛋白磷酸化和聚集是多种神经退行性疾病的特征，包括阿尔茨海默病（AD）。tau 蛋白磷酸化的增加被认为是发病机制中的早期事件，也是聚集和神经原纤维缠结形成的关键方面。然而，tau 蛋白在体内的磷酸化调节及其在 AD 中磷酸化程度增加的原因仍未得到很好的理解，这主要是由于缺乏足够的动物模型。最近，我们描述了在冬眠的欧洲地松鼠中高度磷酸化 tau 蛋白的可逆形成。因此，哺乳动物冬眠是一种非常适合研究在体内生理条件下 tau 磷酸化和去磷酸化的分子机制的模型系统。在这里，我们分析了三种冬眠哺乳动物（北极地松鼠、叙利亚仓鼠和黑熊）的不同脑区中与冬眠状态相关的 tau 磷酸化的程度和动力学。总的来说，tau 蛋白在蛰伏状态下高度磷酸化，并且在所有物种中，在觉醒后磷酸化水平降低。在不同的脑区、冬眠状态和磷酸化位点之间观察到 tau 磷酸化的程度和动力学存在差异。此外，我们测试了 tau 蛋白的磷酸净周转率，以分析在冬眠期间激酶和/或磷酸酶活性的潜在变化。我们的结果表明，tau 蛋白的冬眠状态依赖性磷酸化是特异性调节的，但除了被动的、温度驱动的调节机制外，还涉及到它。通过确定 tau 磷酸化的关键酶的活性状态谱，我们可以鉴定出可能参与冬眠期间发生的差异调节、可逆 tau 磷酸化的激酶。我们表明，在黑熊冬眠与高度磷酸化的 tau 蛋白的构象变化相关，这些变化通常与神经病理学改变有关。黑熊特殊的冬眠特征，即连续的蛰伏期和仅略有降低的体温，因此，可能反映了这种适应反应模式的局限性，因此可能表明这是一种生理过程的过渡状态。
