Glycogen synthase kinase-3beta (GSK3b) is linked to most key aspects of Alzheimer's disease. These include: GSK3b phosphorylates tau and amyloid precursor protein, Abeta peptide activates GSK3b and inhibition of GSK3b protects from Ab-toxicity, and presenilin-1 binds and regulates the activity of GSK3b, actions altered by mutant presenilin-l. Also, GSK3b impairs neural plasticity, facilitates apoptotic signaling cascades, and inhibits the activities of multiple transcription factors (CREB, AP-1, NFkB, myc, b-catenin, and others), all actions likely important in Alzheimer's disease. These actions and associations indicate that GSK3b may be an important modulator of neuropathological processes associated with Alzheimer's disease as well as other neurodegenerative conditions, but much remains to be learned about the actions of GSK3b. The overall goal of this project is to investigate mechanisms regulating GSK3b and to delineate its effects on cell function, especially neural plasticity and apoptosis.
The aims are based on our findings that (i) thapsigargin, which increases intracellular calcium levels and causes endoplasmic reticulum (ER)-stress, conditions associated with Alzheimer's disease, activates GSK3b, and GSK3b is obligatory for thapsigargin-induced apoptosis, (ii) apoptotic stimuli cause intranuclear accumulation of GSK3b, and (iii) GSK3b inhibits the function of the key transcription factor CREB.
Specific Aim 1 will test the hypothesis that GSK3b is activated by, and is a critical mediator of, toxicity induced by thapsigargin and other agents perturbing calcium or the ER, and will identify the mechanisms involved in GSK3b activation and assess the regulatory roles of GSK3b-binding proteins.
Specific Aim 2 will test the hypothesis that apoptotic stimuli induce nuclear accumulation of GSK3b, identify the mechanisms controlling the intranuclear distribution of GSK3b, and test if nuclear GSK3b contributes to apoptotic signaling.
Specific Aim 3 will test the hypothesis that GSK3b has dual functions in apoptosis, both attenuating antiapoptotic signals, with a focus on survival-promoting transcription factors, and facilitating proapoptotic signals connecting ER stress to caspase activation. Overall, these experiments will clarify mechanisms regulating GSK3b and its effects on neural plasticity and survival.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
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Wise, Bradley C
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University of Alabama Birmingham
Schools of Medicine
United States
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Sun, Mianen; Meares, Gordon; Song, Ling et al. (2009) XIAP associates with GSK3 and inhibits the promotion of intrinsic apoptotic signaling by GSK3. Cell Signal 21:1857-65
Yuskaitis, Christopher J; Jope, Richard S (2009) Glycogen synthase kinase-3 regulates microglial migration, inflammation, and inflammation-induced neurotoxicity. Cell Signal 21:264-73
Meares, Gordon P; Zmijewska, Anna A; Jope, Richard S (2008) HSP105 interacts with GRP78 and GSK3 and promotes ER stress-induced caspase-3 activation. Cell Signal 20:347-58
Beurel, Eleonore; Jope, Richard S (2008) Differential regulation of STAT family members by glycogen synthase kinase-3. J Biol Chem 283:21934-44
Sun, M; Song, L; Li, Y et al. (2008) Identification of an antiapoptotic protein complex at death receptors. Cell Death Differ 15:1887-900
Eom, Tae-Yeon; Roth, Kevin A; Jope, Richard S (2007) Neural precursor cells are protected from apoptosis induced by trophic factor withdrawal or genotoxic stress by inhibitors of glycogen synthase kinase 3. J Biol Chem 282:22856-64
Li, Xiaohua; Friedman, Ari B; Zhu, Wawa et al. (2007) Lithium regulates glycogen synthase kinase-3beta in human peripheral blood mononuclear cells: implication in the treatment of bipolar disorder. Biol Psychiatry 61:216-22
Meares, Gordon P; Jope, Richard S (2007) Resolution of the nuclear localization mechanism of glycogen synthase kinase-3: functional effects in apoptosis. J Biol Chem 282:16989-7001
De Sarno, Patrizia; Bijur, Gautam N; Zmijewska, Anna A et al. (2006) In vivo regulation of GSK3 phosphorylation by cholinergic and NMDA receptors. Neurobiol Aging 27:413-22
Jope, Richard S; Roh, Myoung-Sun (2006) Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions. Curr Drug Targets 7:1421-34

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