ABNORMAL TAU-PHOSPHORYLATION AT SER(396) IN ALZHEIMERS-DISEASE RECAPITULATES DEVELOPMENT AND CONTRIBUTES TO REDUCED MICROTUBULE-BINDING
ABNORMAL TAU-PHOSPHORYLATION AT SER(396) IN ALZHEIMERS-DISEASE RECAPITULATES DEVELOPMENT AND CONTRIBUTES TO REDUCED MICROTUBULE-BINDING
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DOI：
10.1016/0896-6273(93)90057-x
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发表时间：
1993-06-01
期刊：
影响因子：
16.2
通讯作者：
LEE, VMY
中科院分区：
文献类型：
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作者：
BRAMBLETT, GT;GOEDERT, M;LEE, VMY
异常磷酸化的tau蛋白（A68）是阿尔茨海默病（AD）成对螺旋丝的构建块。正常成人tau蛋白转化为A68的生物学后果仍然未知。在这里，我们证明，天然A68不结合微管（MT），但脱磷酸化A68恢复的能力，结合MT。Ser396在A68中磷酸化，但在正常成人tau中不磷酸化，而胎儿tau在该位点瞬时磷酸化。在CHO细胞和大鼠脑中，tau蛋白在Ser396处被蛋白激酶磷酸化，产生与A68相似的电泳迁移率。使用转染了Ala396突变体的CHO细胞，我们发现tau蛋白在Ser396的磷酸化降低了其对MT的亲和力，并降低了其稳定MT对诺考达唑诱导解聚的能力。我们的研究结果表明，AD中tau蛋白的异常磷酸化涉及Ser396，我们认为这可能是由胎儿激酶的不适当激活或tau蛋白磷酸酶活性降低介导的。因此，Ser396的磷酸化可能使AD中的MT不稳定，导致受影响细胞的变性。
Abnormally phosphorylated tau proteins (A68) are the building blocks of Alzheimer's disease (AD) paired helical filaments. The biological consequences of the conversion of normal adult tau to A68 remain unknown. Here we demonstrate that native A68 does not bind to microtubules (MTs), yet dephosphorylated A68 regains the ability to bind to MTs. Ser396 is phosphorylated in A68, but not in normal adult tau, whereas fetal tau is phosphorylated transiently at this site. Phosphorylation of tau at Ser396 by protein kinases in CHO cells and rat brain produces an electrophoretic mobility similar to that of A68. Using CHO cells transfected with an Ala396 mutant, we show that the phosphorylation of tau at Ser396 reduces its affinity for MTs and its ability to stabilize MTs against nocodazole-induced depolymerization. Our results demonstrate that the abnormal phosphorylation of tau in AD involves Ser396, and we suggest that this may be mediated by the inappropriate activation of fetal kinases or the reduced activity of tau protein phosphatases. Thus, phosphorylation of Ser396 may destabilize MTs in AD, resulting in the degeneration of affected cells.