Title : N-propanoylmannosamine interferes with
O-GlcNAc modification of the
tyrosine 3-monooxygenase and stimulates dopamine secretion
Abstract :
- The most consistent neurochemical abnormality in Parkinson's disease is degeneration of dopaminergic neurons in the substantia nigra, leading to a reduction of striatal dopamine levels
- The rate-limiting step in the biosynthesis of dopamine, noradrenalin, and adrenalin is catalyzed by tyrosine 3-monooxygenase (=tyrosine hydroxylase ), which catalyzes the formation of L-DOPA
- In earlier studies, we demonstrated that the novel synthetic sialic acid precursor N-propanoylmannosamine is a potent stimulator of axonal growth and promotes reestablishment of the perforant pathway from layer II of cortical neurons to the outer molecular layer of the dentate gyrus
- Here we show that application of N-propanoylmannosamine leads to increased biosynthesis and secretion of dopamine
- This increased biosynthesis of dopamine is due to decreased expression of O-linked N-acetylglucosamine on tyrosine 3-monooxygenase
- Intracellular attachment of O-linked N-acetylglucosamine to serine and threonine residues hinders phosphorylation, thereby regulating the activity of the proteins concerned
- We therefore propose a model in which the application of ManNProp leads to increased phosphorylation and activation of tyrosine 3-monooxygenase, which in turn leads to an increased synthesis of dopamine