Jenkins S M, Johnson G V
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, 35294-0017, USA.
Brain Res. 1997 Sep 5;767(2):305-13. doi: 10.1016/s0006-8993(97)00615-x.
This study examined the phosphorylation of tau on Ser 262, within the first microtubule-binding domain, by a developmentally regulated 100 kDa protein kinase exhibiting significantly greater activity in the embryonic rat brain than in the adult rat brain. This protein kinase co-purified with microtubules and co-immunoprecipitated with both tau and MAP-2. In addition to phosphorylating tau, MAP-2, and a Ser 262-containing peptide, the present protein kinase activity was shown to autophosphorylate as determined by the in-gel kinase assay in the absence of any protein or peptide polymerized into the matrix. Phosphorylation of tau with this protein kinase significantly reduced the tau-microtubule interaction, and the effect was significantly greater with microtubule-associated protein (MAP) preparations from embryonic brain than with preparations from the adult. Ser 262 is phosphorylated extensively in paired helical filament (PHF) tau from Alzheimer's disease (AD) brain, to a lesser extent in fetal tau, and only to a very minor extent in biopsy-derived human tau. Because the 100 kDa protein kinase activity phosphorylates Ser 262 and is higher in the fetal brain than the adult brain, it is hypothesized that an inappropriate re-expression and/or re-activation of this or a similar developmentally regulated protein kinase could contribute to the phosphorylation of Ser 262 in PHF-tau, and thus play a role in the pathogenesis of AD.
本研究检测了一种发育调控的100 kDa蛋白激酶对位于第一个微管结合结构域内的Ser 262位点tau蛋白的磷酸化作用，该蛋白激酶在胚胎大鼠脑中的活性显著高于成年大鼠脑。这种蛋白激酶与微管共纯化，并与tau蛋白和MAP-2共免疫沉淀。除了使tau蛋白、MAP-2和含Ser 262的肽发生磷酸化外，通过在不存在任何聚合到基质中的蛋白质或肽的情况下进行的凝胶内激酶测定表明，该蛋白激酶活性可自身磷酸化。用这种蛋白激酶使tau蛋白磷酸化显著降低了tau蛋白与微管的相互作用，并且胚胎脑来源的微管相关蛋白（MAP）制剂的这种作用显著大于成年脑来源的制剂。在阿尔茨海默病（AD）脑的成对螺旋丝（PHF）tau蛋白中，Ser 262位点被广泛磷酸化，在胎儿tau蛋白中磷酸化程度较低，而在活检获得的人tau蛋白中仅在非常小的程度上被磷酸化。由于100 kDa蛋白激酶活性可使Ser 262位点磷酸化，且在胎儿脑中高于成年脑，因此推测这种或类似的发育调控蛋白激酶的不适当重新表达和/或重新激活可能导致PHF-tau中Ser 262位点的磷酸化，从而在AD的发病机制中起作用。
