Type A monoamine oxidase is the target of an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol, leading to apoptosis in SH-SY5Y cells.
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, DeltaPsim, 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 DeltaPsim 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.
Yi
Hong
H
Department of Neurosciences, Gifu International Institute of Biotechnology, Kakamigahara, Gifu, Japan.
Akao
Yukihiro
Y
Maruyama
Wakako
W
Chen
Kavin
K
Shih
Jean
J
Naoi
Makoto
M
D017209:Apoptosis; D001665:Binding Sites; D045744:Cell Line, Tumor; D004247:DNA; D020868:Gene Silencing; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism; D008995:Monoamine Oxidase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008996:Monoamine Oxidase Inhibitors / Q000378:metabolism*; D009447:Neuroblastoma / Q000473:pathology / Q000503:physiopathology*; D009498:Neurotoxins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012490:Salsoline Alkaloids / Q000378:metabolism*; D044005:Tetrahydroisoquinolines / Q000378:metabolism*; D014162:Transfection
D008996:Monoamine Oxidase Inhibitors; D009498:Neurotoxins; D034741:RNA, Small Interfering; D012490:Salsoline Alkaloids; D044005:Tetrahydroisoquinolines; D004247:DNA; C032837:salsoline; D008995:Monoamine Oxidase