The enzymatic and neurochemical outcomes of a mutation in Mexican cavefish MAO reveal teleost-specific aspects of brain monoamine homeostasis
The enzymatic and neurochemical outcomes of a mutation in Mexican cavefish MAO reveal teleost-specific aspects of brain monoamine homeostasis
Monoamine oxidases (MAO; MAO-A and MAO-B in mammals) are enzymes catalyzing the degradation of biogenic amines, including monoamine neurotransmitters. In humans, coding mutations in MAOs are extremely rare and deleterious. Here, we assessed the structural and biochemical consequences of a point mutation (P106L) in the single mao gene of the blind cavefish Astyanax mexicanus. This mutation decreased mao enzymatic activity by ~3-fold, probably as a result of decreased flexibility in one of the three loops forming the entrance of the active site, thus reducing the access of substrates. HPLC measurements in brains of mutant and non-mutant larvae and adults of the cave and surface morphs of the species showed major disturbances in serotonin, dopamine and noradrenalin (and metabolites) contents in mutants, demonstrating that the P106L mao mutation is fully responsible for monoaminergic disequilibrium in the P106L mao mutant cavefish brain. The outcomes of the mutation were different in the posterior brain (containing the raphe nucleus) and the anterior brain (containing fish-specific hypothalamic serotonergic clusters), revealing contrasting properties in neurotransmitter homeostasis in these different neuronal groups. We also discovered that the effects of the mutation were partially compensated by a decrease in activity of the tph, the serotonin biosynthesis rate-limiting enzyme. Finally, the neurochemical outcomes of the mao P106L mutation differed in many respects from a treatment with deprenyl, an irreversible MAO inhibitor, showing that genetic and pharmacological interference with MAO function are not the same. Our results shade light on our understanding of cavefish evolution, on the specificities of fish monoaminergic systems, and on MAO-dependent homeostasis of brain neurochemistry in general.
Pierre Constance、Callebert Jacques、Retaux Sylvie、Launay Jean-Marie
基础医学生物化学神经病学、精神病学
Pierre Constance,Callebert Jacques,Retaux Sylvie,Launay Jean-Marie.The enzymatic and neurochemical outcomes of a mutation in Mexican cavefish MAO reveal teleost-specific aspects of brain monoamine homeostasis[EB/OL].(2025-03-28)[2025-04-29].https://www.biorxiv.org/content/10.1101/2022.10.10.511577.点此复制
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