Hamdane Malika, Dourlen Pierre, Bretteville Alexis, Sambo Anne-Véronique, Ferreira Stéphanie, Ando Kunie, Kerdraon Olivier, Bégard Séverine, Geay Linda, Lippens Guy, Sergeant Nicolas, Delacourte André, Maurage Claude-Alain, Galas Marie-Christine, Buée Luc
Inserm, U815, Institut de Médecine Prédictive et Recherche Thérapeutique, F-59045 Lille, France.
Mol Cell Neurosci. 2006 May-Jun;32(1-2):155-60. doi: 10.1016/j.mcn.2006.03.006. Epub 2006 May 11.
Neurofibrillary degeneration is likely to be related to abnormal Tau phosphorylation and aggregation. Among abnormal Tau phosphorylation sites, pThr231 is of particular interest since it is associated with early stages of Alzheimer's disease and is a binding site of Pin1, a peptidyl-prolyl cis/trans isomerase mainly involved in cell cycle regulation. In the present work, Pin1 level was found strongly increased during neuronal differentiation and tightly correlated with Tau dephosphorylation at Thr231. Likewise, we showed in cellular model that Pin1 allowed for specific Tau dephosphorylation at Thr231, whereas other phosphorylation sites were unchanged. Moreover, cells displaying Tau phosphorylation at Thr231 did not show any Pin1 nuclear depletion. Altogether, these data indicate that Pin1 has key function(s) in neuron and is at least involved in the regulation of Tau phosphorylation at relevant sites. Hence, Pin1 dysfunction, unlikely by nuclear depletion, may have critical consequences on Tau pathological aggregation and neuronal death.
神经原纤维变性可能与异常的 Tau 蛋白磷酸化和聚集有关。在异常的 Tau 蛋白磷酸化位点中，pThr231 特别引人关注，因为它与阿尔茨海默病的早期阶段相关，并且是 Pin1 的结合位点，Pin1 是一种主要参与细胞周期调控的肽基脯氨酰顺/反异构酶。在本研究中，发现 Pin1 水平在神经元分化过程中显著升高，并且与 Thr231 位点的 Tau 蛋白去磷酸化密切相关。同样，我们在细胞模型中表明，Pin1 能够使 Thr231 位点发生特异性的 Tau 蛋白去磷酸化，而其他磷酸化位点则保持不变。此外，在 Thr231 位点出现 Tau 蛋白磷酸化的细胞并未表现出任何 Pin1 的核内缺失。综上所述，这些数据表明 Pin1 在神经元中具有关键作用，并且至少参与了相关位点 Tau 蛋白磷酸化的调节。因此，Pin1 功能障碍（不太可能是由于核内缺失）可能对 Tau 蛋白的病理性聚集和神经元死亡产生关键影响。
