Zawiślak Alina, Jakimowicz Piotr, McCubrey James A, Rakus Dariusz
Department of Physiology and Molecular Neurobiology, Faculty of Biological Sciences, University of Wroclaw, Wroclaw, Poland.
Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland.
Oncotarget. 2017 Nov 20;8(63):106625-106638. doi: 10.18632/oncotarget.22542. eCollection 2017 Dec 5.
It has been shown that neurons alter the expression of astrocytic metabolic enzymes by secretion of until now unknown molecule(s) into extracellular fluid. Here, we present evidence that neuron-derived transthyretin (TTR) stimulates expression of glycolytic enzymes in astrocytes which is reflected by an increased synthesis of ATP. The action of TTR is restricted to regulatory enzymes of glycolysis: phosphofructokinase P (PFKP) and pyruvate kinase M1/M2 isoforms (PKM1/2). The regulation of PFK and PKM expression by TTR is presumably specific for brain tissue and is independent of the role of TTR as a carrier protein for thyroxine and retinol. TTR induced expression of PKM and PFK is mediated by the cAMP/PKA-dependent pathway and is antagonized by the PI3K/Akt pathway. Our results provide the first experimental evidence for action of TTR as a neuron-derived energy metabolism activator in astrocytes and describe the mechanisms of its action. The data presented here suggest that TTR is involved in a mechanism in which neurons stimulate degradation of glycogen-derived glucosyl units without significant modulation of glucose uptake by glial cells.
研究表明，神经元通过向细胞外液分泌迄今未知的分子来改变星形胶质细胞代谢酶的表达。在此，我们提供证据表明，神经元衍生的转甲状腺素蛋白（TTR）刺激星形胶质细胞中糖酵解酶的表达，这表现为ATP合成增加。TTR的作用仅限于糖酵解的调节酶：磷酸果糖激酶P（PFKP）和丙酮酸激酶M1/M2亚型（PKM1/2）。TTR对PFK和PKM表达的调节可能是脑组织特有的，且独立于TTR作为甲状腺素和视黄醇载体蛋白的作用。TTR诱导的PKM和PFK表达由cAMP/PKA依赖性途径介导，并受到PI3K/Akt途径的拮抗。我们的结果为TTR作为神经元衍生的星形胶质细胞能量代谢激活剂的作用提供了首个实验证据，并描述了其作用机制。此处呈现的数据表明，TTR参与了一种机制，即神经元刺激糖原衍生的葡萄糖基单位的降解，而对神经胶质细胞摄取葡萄糖没有显著调节作用。
