Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase 1 glycogen synthase kinase 3 beta in brain
Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase 1 glycogen synthase kinase 3 beta in brain
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DOI：
10.1073/pnas.93.7.2719
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发表时间：
1996-04-02
影响因子：
11.1
通讯作者：
Imahori, K
中科院分区：
文献类型：
--
作者：
Hoshi, M;Takashima, A;Imahori, K
根据阿尔茨海默病发病机制的淀粉样蛋白假说，β-淀粉样蛋白肽（beta-amyloid peptide，beta A）直接影响神经元，导致神经元变性和tau蛋白磷酸化，在大鼠海马培养中，beta A暴露激活tau蛋白激酶I/糖原合成酶激酶3 β（TPKI/GSK-3 β），其将tau蛋白磷酸化为阿尔茨海默病样形式，导致神经元死亡，为了阐明β A诱导神经元死亡的机制，我们在双杂交系统中寻找TPKI/GSK-3 β的底物，并鉴定了丙酮酸脱氢酶（PDH），其在线粒体中将丙酮酸转化为乙酰辅酶A。PDH在体外被TPKI/GSK-3 β磷酸化并失活，在β A处理的海马培养物中也是如此，导致线粒体功能障碍，这将有助于神经元死亡。在胆碱能神经元中，β A损害乙酰胆碱合成而不影响胆碱乙酰转移酶活性，这表明PDH被β A诱导的TPKI/GSK-3 β失活。因此，TPKI/GSK-3 β调节PDH并参与能量代谢和乙酰胆碱合成，提示TPKI/GSK-3 β在阿尔茨海默病的发病机制中起关键作用。
According to the amyloid hypothesis for the pathogenesis of Alzheimer disease, beta-amyloid peptide (beta A) directly affects neurons, leading to neurodegeneration and tau phosphorylation, In rat hippocampal culture, beta A exposure activates tau protein kinase I/glycogen synthase kinase 3 beta (TPKI/GSK-3 beta), which phosphorylates tau protein into Alzheimer disease-like forms, resulting in neuronal death, To elucidate the mechanism of beta A-induced neuronal death, we searched for substrates of TPKI/GSK-3 beta in a two-hybrid system and identified pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA In mitochondria. PDH was phosphorylated and inactivated by TPKI/GSK-3 beta in vitro and also In beta A-treated hippocampal cultures, resulting in mitochondrial dysfunction, which would contribute to neuronal death, In cholinergic neurons, beta A impaired acetylcholine synthesis without affecting choline acetyltransferase activity, which suggests that PDH is inactivated by beta A-induced TPKI/GSK-3 beta. Thus, TPKI/GSK-3 beta regulates PDH and participates in energy metabolism and acetylcholine synthesis, These results suggest that TPKI/GSK-3 beta plays a key role in the pathogenesis of Alzheimer disease.