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- Title
In vivo activation and nuclear translocation of phosphorylated glycogen synthase kinase-3β in neuronal apoptosis: links to tau phosphorylation.
- Authors
Elyaman, W.; Terro, F.; Wong, N. S.; Hugon, J.
- Abstract
Abstract The roles of glycogen synthase kinase-3β (GSK-3β) and tau phosphorylation were examined in seven-day-old rats injected with the NMDA receptor antagonist (MK801) that is known to induce neuronal apoptosis. Immunoblot and immunohistochemical analysis of brain samples demonstrated a site-specific increase in tau phosphorylation associated with the relocalization of the protein to the nuclear/perinuclear region of apoptotic neurons. In addition, a tau 32-kDa fragment was detected, suggesting that tau was a target of intracellular proteolysis in MK801-treated brains. The proteolytically modified form of tau has reduced ability to bind to microtubules. GSK-3β kinase assay and immunoblottings of active (tyrosine-216) and inactive (serine-9) forms of GSK-3β revealed a rapid and transient increase in the kinase activity. Lithium chloride, a GSK-3β inhibitor, prevented tau phosphorylation suggesting that tau phosphorylation is mediated by the activation of GSK-3β. Confocal microscopy using double labelling of tau and GSK--3β revealed that the activation of GSK-3β in neurons was associated with early (2 h) nuclear translocation of tyrosine-216 GSK-3β. The execution phase of neuronal apoptosis was accompanied by a selective phosphorylation of serine-9 and dephosphorylation of tyrosine-216 GSK-3β. These findings demonstrate that in vivo , GSK-3β kinase activation and nuclear translocation are early stress signals of neuronal apoptosis.
- Subjects
PROTEIN kinases; NEURONS; APOPTOSIS
- Publication
European Journal of Neuroscience, 2002, Vol 15, Issue 4, p651
- ISSN
0953-816X
- Publication type
Article
- DOI
10.1046/j.1460-9568.2002.01899.x