Neurodegenerative diseases are characterized by the accumulation of specific phosphorylated protein aggregates in the brain, such as hyperphosphorylated tau (hp-tau) in tauopathies and phosphorylated α-synuclein (p-αSyn) in α-synucleinopathies. The simultaneous accumulation of different proteins is a common event in many neurodegenerative diseases. We herein describe the detection of the phosphorylation and dimerization of αSyn and activation of GSK-3β, a major kinase known to phosphorylate tau and αSyn, in the brains of rTg4510 mice that overexpress human P301L mutant tau. Immunohistochemistry showed p-αSyn aggregates in rTg4510 mice, which were suppressed by doxycycline-mediated decreases in mutant tau expression levels. A semi-quantitative analysis revealed a regional correlation between hp-tau and p-αSyn accumulation in rTg4510 mice. Furthermore, proteinase K-resistant αSyn aggregates were found in the region with excessive hp-tau accumulation in rTg4510 mice, and these aggregates were morphologically different from proteinase K-susceptible p-αSyn aggregates. Western blotting revealed decreases in p-αSyn monomers in TBS- and sarkosyl-soluble fractions and increases in ubiquitinated p-αSyn dimers in sarkosyl-soluble and insoluble fractions in rTg4510 mice. Furthermore, an activated form of GSK-3β was immunohistochemically detected within cells containing both hp-tau and p-αSyn aggregates. A semi-quantitative analysis revealed that increased GSK-3β activity strongly correlated with hp-tau and p-αSyn accumulation in rTg4510 mice. Collectively, the present results suggest that the overexpression of human P301L mutant tau promoted the phosphorylation and dimerization of endogenous αSyn by activating GSK-3β in rTg4510 mice. This synergic effect between tau, αSyn, and GSK-3β may be involved in the pathophysiology of several neurodegenerative diseases that show the accumulation of both tau and αSyn.

中文翻译：

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在tTg4510小鼠tauopathy模型中，α-突触核蛋白的磷酸化和寡聚化与GSK-3β激活相关。

神经退行性疾病的特征是大脑中特定的磷酸化蛋白质聚集物的积累，例如牛海绵状脑病中的高磷酸化tau（hp-tau）和α-突触核细胞病中的磷酸化α-突触核蛋白（p-αSyn）。在许多神经退行性疾病中，不同蛋白质的同时积累是常见事件。我们在此描述了在过度表达人P301L突变体tau的rTg4510小鼠的大脑中检测到αSyn的磷酸化和二聚化以及激活GSK-3β（一种已知的磷酸化tau和αSyn的主要激酶）的激活。免疫组织化学显示在rTg4510小鼠中p-αSyn聚集体被强力霉素介导的突变体tau表达水平下降所抑制。半定量分析显示rTg4510小鼠中hp-tau和p-αSyn积累之间存在区域相关性。此外，在rTg4510小鼠中，在hp-tau过多的区域发现了耐蛋白酶K的αSyn聚集体，这些聚集体在形态上不同于蛋白酶K敏感的p-αSyn聚集体。Western印迹显示，rTg4510小鼠的TBS和可溶鲨糖基可溶级分中的p-αSyn单体减少，而在可溶鲨糖基和不可溶级分中泛素化的p-αSyn二聚体增加。此外，在含有hp-tau和p-αSyn聚集体的细胞中免疫组化检测到GSK-3β的活化形式。半定量分析显示，增加的GSK-3β活性与rTg4510小鼠中的hp-tau和p-αSyn积累密切相关。总的来说，目前的结果表明，人P301L突变体tau的过表达通过激活rTg4510小鼠中的GSK-3β促进了内源性αSyn的磷酸化和二聚化。tau，αSyn和GSK-3β之间的这种协同作用可能与几种显示tau和αSyn积累的神经退行性疾病的病理生理有关。