Bush M L, Miyashiro J S, Ingram V M
Department of Biology, Massachusetts Institute of Technology, Cambridge 02139.
Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):1861-5. doi: 10.1073/pnas.92.6.1861.
Brain pathology in Alzheimer disease and in aged controls shows hyperphosphorylation of tau and of neurofilament proteins. Roder and Ingram [Roder, H.M. & Ingram, V.M. (1991) J. Neurosci. 11, 3325-3343 and Roder, H.M., Eden, P.A. & Ingram, V.M. (1993) Biochem. Biophys. Res. Commun. 193, 639-647] previously reported that the brain protein kinase PK40erk can hyperphosphorylate both tau and neurofilaments and interestingly, is strongly inhibited by ATP uncomplexed with Mg2+. We now report that the mitochondrial uncoupler carbonyl cyanide p-trifluoro-methoxyphenylhydrazone decreases ATP levels in rat pheochromacytoma (PC-12) cells differentiated with nerve growth factor and activates a neurofilament kinase, a tau kinase, and, unexpectedly, a tau phosphatase--either PP1 or PP2A. Such aberrant modulation of protein phosphorylation patterns could be the common biochemical basis for senile dementia and for Alzheimer disease and could explain the late-onset etiology of both conditions.
阿尔茨海默病及老年对照者的脑病理学研究显示，tau蛋白和神经丝蛋白存在过度磷酸化现象。罗德尔和英格拉姆[罗德尔，H.M. & 英格拉姆，V.M.（1991年）《神经科学杂志》11卷，3325 - 3343页；罗德尔，H.M.，伊登，P.A. & 英格拉姆，V.M.（1993年）《生物化学与生物物理研究通讯》193卷，639 - 647页]此前报道，脑蛋白激酶PK40erk可使tau蛋白和神经丝蛋白均发生过度磷酸化，有趣的是，它会受到未与Mg2 +结合的ATP的强烈抑制。我们现在报道，线粒体解偶联剂对三氟甲氧基苯腙可降低经神经生长因子分化的大鼠嗜铬细胞瘤（PC - 12）细胞中的ATP水平，并激活一种神经丝激酶、一种tau激酶，以及出乎意料的一种tau磷酸酶——PP1或PP2A。这种蛋白质磷酸化模式的异常调节可能是老年痴呆和阿尔茨海默病的共同生化基础，并且可以解释这两种病症的迟发性病因。
