A1 Refereed original research article in a scientific journal

The Wnt pool of glycogen synthase kinase 3 beta is critical for trophic-deprivation-induced neuronal death




AuthorsHongisto V, Vainio JC, Thompson R, Courtney MJ, Coffey ET

PublisherAMER SOC MICROBIOLOGY

Publication year2008

JournalMolecular and Cellular Biology

Journal name in sourceMOLECULAR AND CELLULAR BIOLOGY

Journal acronymMOL CELL BIOL

Volume28

Issue5

First page 1515

Last page1527

Number of pages13

ISSN0270-7306

DOIhttps://doi.org/10.1128/MCB.02227-06


Abstract
Glycogen synthase kinase 3 (GSK-3) is implicated in neuronal death through a causal role, and precise mechanisms have not been unambiguously defined. We show that short hairpin RNA (shRNA) knockdown of GSK-3 beta, but not GSK-3 alpha, protects cerebellar granule neurons from trophic-deprivation-induced death. Using compartment-targeted inhibitors of the Wnt-regulated GSK-3 pool, NLS-FRAT1, NES-FRAT1, and axin-GSK-3-interacting domain (axin-GID), we locate proapoptotic GSK-3 action to the cytosol and regulation of Bim protein turnover despite constitutive cycling of GSK-3 between the cytosol and nucleus, revealed by leptomycin B. We examine the importance of Ser21/9 (GSK-3 alpha/beta) phosphorylation on proapoptotic GSK-3 function. Neurons isolated from GSK-3 alpha/beta(S21A/S9A) knock-in mice survive normally and are fully sensitive to trophic-deprivation-induced death. Nonetheless, inhibition of GSK-3 catalytic activity with lithium or SB216763 protects GSK-3 alpha/beta(S21A/S9A) neurons from death. This indicates that dephosphorylation of GSK-3 beta/Ser9 and GSK-3 alpha/Ser21 is insufficient for GSK-3 proapoptotic function and that another level of regulation is required. Gel filtration reveals a stress-induced loss of neuronal GSK-3 beta from a high-molecular-mass complex with a concomitant decrease in axin-bound GSK-3 beta. These data imply that Wnt-regulated GSK-3 beta plays a nonredundant role in trophic-deprivation-induced death of neurons.



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