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Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain.

机译:大脑中tau蛋白激酶I /糖原合酶激酶3beta对线粒体丙酮酸脱氢酶活性的调节。

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摘要

According to the amyloid hypothesis for the pathogenesis of Alzheimer disease, beta-amyloid peptide (betaA) directly affects neurons, leading to neurodegeneration and tau phosphorylation. In rat hippocampal culture, betaA exposure activates tau protein kinase I/glycogen synthase kinase 3beta (TPKI/GSK-3beta), which phosphorylates tau protein into Alzheimer disease-like forms, resulting in neuronal death. To elucidate the mechanism of betaA-induced neuronal death, we searched for substrates of TPKI/GSK-3beta 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-3beta in vitro and also in betaA-treated hippocampal cultures, resulting in mitochondrial dysfunction, which would contribute to neuronal death. In cholinergic neurons, betaA impaired acetylcholine synthesis without affecting choline acetyltransferase activity, which suggests that PDH is inactivated by betaA-induced TPKI/GSK-3beta. Thus, TPKI/GSK-3beta regulates PDH and participates in energy metabolism and acetylcholine synthesis. These results suggest that TPKI/GSK-3beta plays a key role in the pathogenesis of Alzheimer disease.
机译:根据阿尔茨海默氏病发病机理的淀粉样假说,β-淀粉样肽(betaA)直接影响神经元,导致神经变性和tau磷酸化。在大鼠海马培养物中,betaA暴露会激活tau蛋白激酶I /糖原合酶激酶3beta(TPKI / GSK-3beta),后者会将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βA诱导的神经元死亡的机制,我们在两个杂交系统中搜索了TPKI / GSK-3beta的底物,并鉴定了丙酮酸脱氢酶(PDH),该酶在线粒体中将丙酮酸转化为乙酰辅酶A。 PDH在体外以及在经betaA处理的海马培养物中均被TPKI / GSK-3beta磷酸化并失活,导致线粒体功能障碍,这将导致神经元死亡。在胆碱能神经元中,betaA会破坏乙酰胆碱的合成,而不会影响胆碱乙酰基转移酶的活性,这表明PDH被betaA诱导的TPKI / GSK-3beta灭活。因此,TPKI / GSK-3beta调节PDH并参与能量代谢和乙酰胆碱合成。这些结果表明,TPKI / GSK-3beta在阿尔茨海默氏病的发病机理中起着关键作用。

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