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N ‐Propanoylmannosamine interferes with O‐GlcNAc modification of the tyrosine 3‐monooxygenase and stimulates dopamine secretion
Author(s) -
Bork Kaya,
Kannicht Christoph,
Nöhring Sabine,
Reutter Werner,
Weidemann Wenke,
Hart Gerald W.,
Horstkorte Rüdiger
Publication year - 2007
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.21526
Subject(s) - dopamine , tyrosine hydroxylase , tyrosine , dopaminergic , neurochemical , substantia nigra , chemistry , tyrosine 3 monooxygenase , biochemistry , phosphorylation , serine , tyrosine phosphorylation , endocrinology , medicine , biology
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. © 2007 Wiley‐Liss, Inc.