Type A monoamine oxidase is the target of an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol, leading to apoptosis in SH-SY5Y cells
Type A monoamine oxidase is the target of an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol, leading to apoptosis in SH-SY5Y cells
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DOI：
10.1111/j.1471-4159.2005.03573.x
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发表时间：
2006-01-01
影响因子：
4.7
通讯作者：
Naoi, M
中科院分区：
文献类型：
--
作者：
Yi, H;Akao, Y;Naoi, M
线粒体单胺氧化酶（MAO）被认为通过增加氧化应激或用B型MAO抑制剂（MAO-B）保护而参与神经元变性。本研究以人神经母细胞瘤SH-SY 5 Y细胞为研究对象，研究了A型单胺氧化酶（MAO-A）在细胞凋亡中的作用。内源性多巴胺能神经毒素N-甲基（R）猪毛菜醇（一种MAO-A抑制剂）可降低分离线粒体的膜电位Δ Psim，并诱导细胞凋亡，而MAO-A底物5-羟色胺可阻止这种凋亡。相反，β-苯乙胺，一种MAO-B底物，不抑制N-甲基（R）猪毛菜醇引起的Δ Psi m下降。MOA-A抑制剂clorgyline可抑制N-甲基（R）猪毛菜醇与线粒体的结合，而MAO-B抑制剂（-）deprenyl则不抑制。靶向MAO-A的RNA干扰显著降低了N-甲基（R）猪毛菜醇的结合，同时降低了MAO活性。为了检测MAO-B在凋亡过程中的干预，将人MAO-B转染到SH-SY 5 Y细胞中，但对N-甲基（R）猪毛菜醇的敏感性不受影响，即使MAO的活性和蛋白质显著增加。这些结果证明了MAO-A在神经毒素结合和诱导细胞凋亡中的新功能，这可能是神经退行性疾病（包括帕金森病）中神经元细胞死亡的原因。
Mitochondrial monoamine oxidase (MAO) has been considered to be involved in neuronal degeneration either by increased oxidative stress or protection with the inhibitors of type B MAO (MAO-B). In this paper, the role of type A MAO (MAO-A) in apoptosis was studied using human neuroblastoma SH-SY5Y cells, where only MAO-A is expressed. An endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol, an MAO-A inhibitor, reduced membrane potential, Delta Psi m, in isolated mitochondria, and induced apoptosis in the cells, which 5-hydroxytryptamine, an MAO-A substrate, prevented. In contrast, beta-phenylethylamine, an MAO-B substrate, did not suppress the Delta Psi m decline by N-methyl(R)salsolinol. The binding of N-methyl(R)salsolinol to mitochondria was inhibited by clorgyline, a MOA-A inhibitor, but not by (-)deprenyl, an MAO-B inhibitor. RNA interference targeting MAO-A significantly reduced the binding of N-methyl(R)salsolinol with simultaneous reduction in the MAO activity. To examine the intervention of MAO-B in the apoptotic process, human MAO-B was transfected to SH-SY5Y cells, but the sensitivity to N-methyl(R)salsolinol was not affected, even although the activity and protein of MAO increased markedly. These results demonstrate a novel function of MAO-A in the binding of neurotoxins and the induction of apoptosis, which may account for neuronal cell death in neurodegenerative disorders, including Parkinson's disease.