NEURONAL SIGNALING--OXIDANTS AND ALZHEIMERS DISEASE

Summary

Principal Investigator: RICHARD JOPE
Affiliation: University of Alabama at Birmingham
Country: USA
Abstract: Because of the association of oxidative stress with widespread debilitating disorders of the CNS, it is imperative to identify how signaling systems are affected by oxidative stress. This project is focused on testing specific hypotheses concerning the effects of oxidative stress on signaling systems linked to cholinergic muscarinic receptors. These receptors are coupled to the phosphoinositide (PI) signal transduction system, increases in protein tyrosine phosphorylation, and downstream transcription factor modulation. Deficient PI signaling has been reported in Alzheimer's disease, which is centered on dysfunction of the G- proteins that mediate signal transduction. Human neuroblastoma SH-SY5Y cells provide an optimal model system to study because they express m3 muscarinic receptors which mediate robust stimulation of the PI signal transduction system, intracellular increases in protein tyrosine phosphorylation, and activation of transcription factors such as AP-1 and NFkappaB, each of which appears to be important in cellular responses to oxidative stress. The overall goal is to test the hypothesis that oxidative stress modulates specific sites in these three signaling components, PI hydrolysis, protein tyrosine phosphorylation, and transcription factor activation. Three complementary approaches will be used to model oxidative stress, exposure of SH-SY5Y cells to (a) H2O2, or (b) peroxynitrite, or (c) the use of "cybrid" SH-SY5Y cells in which endogenous mitochondria have been replaced with mitochondria from Alzheimer's disease or matched control subjects. The Alzheimer's disease-derived cybrid cells thus possess defective cytochrome c oxidase and produce excessive reactive oxygen species. Specific Aim 1 will test the hypotheses that oxidative stress impairs muscarinic receptor-induced PI hydrolysis and that inhibition of the G-protein Gq/11 is a critical site of action. Specific Aim 2 will test the hypotheses that oxidative agents impair the palmitoylation of cysteines on the G-protein Gq/11 and that inhibition of Gq/11 palmitoylation impairs PI hydrolysis. Specific Aim 3 will test the hypotheses that oxidative stress alters intracellular protein tyrosine phosphorylation, including substrates responding to muscarinic stimulation. Specific Aim 4 will test the hypothesis that oxidative agents inhibit the tyrosine phosphorylation of Gq/11 and will test if this is associated with inhibition of Gq/11 palmitoylation. Specific Aim 5 will terst the hypothesis that oxidative agents modulate transcription factor activation, including those activated by muscarinic receptor stimulation.
Funding Period: 1999-07-01 - 2003-06-30
more information: NIH RePORT

Top Publications

  1. pmc Anesthesia and post-mortem interval profoundly influence the regulatory serine phosphorylation of glycogen synthase kinase-3 in mouse brain
    Xiaohua Li
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, 1720 7th Avenue South, Birmingham, AL 35294 0017, USA
    J Neurochem 92:701-4. 2005
  2. pmc Glycogen synthase kinase-3 regulates microglial migration, inflammation, and inflammation-induced neurotoxicity
    Christopher J Yuskaitis
    Department of Psychiatry and Behavioral Neurobiology, 1720 Seventh Avenue South, Sparks Center 1057, University of Alabama at Birmingham, Birmingham, AL 35294 0017, USA
    Cell Signal 21:264-73. 2009
  3. pmc Lithium prevents and ameliorates experimental autoimmune encephalomyelitis
    Patrizia De Sarno
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham, AL 35294, USA
    J Immunol 181:338-45. 2008
  4. pmc Differential regulation of STAT family members by glycogen synthase kinase-3
    Eleonore Beurel
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham, Alabama 35294 0017, USA
    J Biol Chem 283:21934-44. 2008
  5. pmc Neural precursor cells are protected from apoptosis induced by trophic factor withdrawal or genotoxic stress by inhibitors of glycogen synthase kinase 3
    Tae Yeon Eom
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294 0017, USA
    J Biol Chem 282:22856-64. 2007
  6. pmc Resolution of the nuclear localization mechanism of glycogen synthase kinase-3: functional effects in apoptosis
    Gordon P Meares
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294 0017, USA
    J Biol Chem 282:16989-7001. 2007
  7. pmc Mitochondrial-targeted active Akt protects SH-SY5Y neuroblastoma cells from staurosporine-induced apoptotic cell death
    Paramita Mookherjee
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
    J Cell Biochem 102:196-210. 2007
  8. pmc Tau is hyperphosphorylated at multiple sites in mouse brain in vivo after streptozotocin-induced insulin deficiency
    Buffie J Clodfelder-Miller
    Department of Psychiatry and Behavioral Neurobiology, 1720 Seventh Ave South, Sparks Center 1057, University of Alabama, Birmingham, AL 35294 0017, USA
    Diabetes 55:3320-5. 2006
  9. pmc Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions
    Richard S Jope
    Department of Psychiatry and Behavioral Neurobiology, Sparks Center 1057, University of Alabama at Birmingham, Birmingham, AL 35294 0017, USA
    Curr Drug Targets 7:1421-34. 2006
  10. pmc Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics
    Richard S Jope
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Sparks Center 1057, 1720 Seventh Avenue South, Birmingham, AL 35294 0017, USA
    Neurochem Res 32:577-95. 2007

Scientific Experts

  • Patrizia De Sarno
  • Eleonore Beurel
  • RICHARD JOPE
  • Ling Song
  • Anna A Zmijewska
  • Myoung Sun Roh
  • Tae Yeon Eom
  • Christopher J Yuskaitis
  • Gordon P Meares
  • Paramita Mookherjee
  • Gail V W Johnson
  • Kevin A Roth
  • Buffie J Clodfelder-Miller
  • Taj D King
  • Xiaohua Li
  • Michael Martin
  • Buffie Clodfelder-Miller
  • Rodrigo Quintanilla
  • Kunal Rehani
  • Suzanne M Michalek
  • Ari B Friedman

Detail Information

Publications19

  1. pmc Anesthesia and post-mortem interval profoundly influence the regulatory serine phosphorylation of glycogen synthase kinase-3 in mouse brain
    Xiaohua Li
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, 1720 7th Avenue South, Birmingham, AL 35294 0017, USA
    J Neurochem 92:701-4. 2005
    ....
  2. pmc Glycogen synthase kinase-3 regulates microglial migration, inflammation, and inflammation-induced neurotoxicity
    Christopher J Yuskaitis
    Department of Psychiatry and Behavioral Neurobiology, 1720 Seventh Avenue South, Sparks Center 1057, University of Alabama at Birmingham, Birmingham, AL 35294 0017, USA
    Cell Signal 21:264-73. 2009
    ..These findings demonstrate that GSK3 promotes microglial responses to inflammation and that the utilization of GSK3 inhibitors provides a means to limit the inflammatory actions of microglia...
  3. pmc Lithium prevents and ameliorates experimental autoimmune encephalomyelitis
    Patrizia De Sarno
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham, AL 35294, USA
    J Immunol 181:338-45. 2008
    ....
  4. pmc Differential regulation of STAT family members by glycogen synthase kinase-3
    Eleonore Beurel
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham, Alabama 35294 0017, USA
    J Biol Chem 283:21934-44. 2008
    ..Thus, inhibitors of GSK3 reduce the activation of STAT3 and STAT5, providing a mechanism to differentially regulate STATs to modulate the inflammatory response...
  5. pmc Neural precursor cells are protected from apoptosis induced by trophic factor withdrawal or genotoxic stress by inhibitors of glycogen synthase kinase 3
    Tae Yeon Eom
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294 0017, USA
    J Biol Chem 282:22856-64. 2007
    ..Thus, NPCs are sensitive to loss of trophic factors and genotoxic stress, and inhibitors of GSK3 are capable of enhancing NPC survival...
  6. pmc Resolution of the nuclear localization mechanism of glycogen synthase kinase-3: functional effects in apoptosis
    Gordon P Meares
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294 0017, USA
    J Biol Chem 282:16989-7001. 2007
    ..Identification of a GSK3beta NLS allows new strategies to decipher and manipulate its subcellular actions regulating gene expression and apoptosis and its involvement in diseases...
  7. pmc Mitochondrial-targeted active Akt protects SH-SY5Y neuroblastoma cells from staurosporine-induced apoptotic cell death
    Paramita Mookherjee
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
    J Cell Biochem 102:196-210. 2007
    ..These findings demonstrate that intramitochondrial active Akt results in efficient protection against apoptotic signaling...
  8. pmc Tau is hyperphosphorylated at multiple sites in mouse brain in vivo after streptozotocin-induced insulin deficiency
    Buffie J Clodfelder-Miller
    Department of Psychiatry and Behavioral Neurobiology, 1720 Seventh Ave South, Sparks Center 1057, University of Alabama, Birmingham, AL 35294 0017, USA
    Diabetes 55:3320-5. 2006
    ....
  9. pmc Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions
    Richard S Jope
    Department of Psychiatry and Behavioral Neurobiology, Sparks Center 1057, University of Alabama at Birmingham, Birmingham, AL 35294 0017, USA
    Curr Drug Targets 7:1421-34. 2006
    ..In part because of these key actions of GSK3 and its associations with mood disorders and schizophrenia, much research is currently being devoted to identifying new selective inhibitors of GSK3...
  10. pmc Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics
    Richard S Jope
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Sparks Center 1057, 1720 Seventh Avenue South, Birmingham, AL 35294 0017, USA
    Neurochem Res 32:577-95. 2007
    ..Thus, GSK3 may contribute not only to primary pathologies in these diseases, but also to the associated inflammation, suggesting that GSK3 inhibitors may have multiple effects influencing these conditions...
  11. pmc The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways
    Eleonore Beurel
    Department of Psychiatry and Behavioral Neurobiology, Sparks Center 1057, University of Alabama at Birmingham, Birmingham, AL 35294 0017, USA
    Prog Neurobiol 79:173-89. 2006
    ....
  12. pmc Cellular stress increases RGS2 mRNA and decreases RGS4 mRNA levels in SH-SY5Y cells
    Ling Song
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Sparks Center 1057, Birmingham, AL 35294 0017, USA
    Neurosci Lett 402:205-9. 2006
    ..Overall, these results indicate that cell cycle arrest regulates the expression of RGS2 and RGS4, and that the expression of these two RGS family members is oppositely regulated by stress that causes cell cycle arrest...
  13. pmc AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3
    Taj D King
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294 0017, USA
    Biochem Pharmacol 71:1637-47. 2006
    ....
  14. pmc In vivo regulation of GSK3 phosphorylation by cholinergic and NMDA receptors
    Patrizia De Sarno
    Department of Psychiatry and Behavioral Neurobiology, 1720 Seventh Ave South, Sparks Center 1057, University of Alabama at Birmingham, Birmingham, AL 35294 0017, USA
    Neurobiol Aging 27:413-22. 2006
    ..Thus, drugs in each class of therapeutic agents used for AD have the common property of increasing the regulatory serine-phosphorylation of GSK3 within common pools of the enzyme...
  15. pmc Physiological and pathological changes in glucose regulate brain Akt and glycogen synthase kinase-3
    Buffie Clodfelder-Miller
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294 0017, USA
    J Biol Chem 280:39723-31. 2005
    ..Thus, the Akt-GSK3 signaling pathway is regulated in mouse brain in vivo in response to physiological and pathological changes in insulin and glucose...
  16. pmc Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3
    Michael Martin
    Department of Oral Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294 2170, USA
    Nat Immunol 6:777-84. 2005
    ..These findings demonstrate a regulatory function for GSK3 in modulating the inflammatory response...
  17. ncbi Anti-apoptotic effects of muscarinic receptor activation are mediated by Rho kinase
    Patrizia De Sarno
    Department of Psychiatry and Behavioral Neurobiology, 1720 Seventh Avenue South, Sparks Center 1057, University of Alabama at Birmingham, Birmingham, AL 35294 0017, USA
    Brain Res 1041:112-5. 2005
    ..These results demonstrate that the anti-apoptotic effect provided by muscarinic receptor stimulation is dependent on the activity of Rho kinase...
  18. ncbi Hypoxia activates glycogen synthase kinase-3 in mouse brain in vivo: protection by mood stabilizers and imipramine
    Myoung Sun Roh
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294 0017, USA
    Biol Psychiatry 57:278-86. 2005
    ....
  19. pmc Lipopolysaccharide-induced interleukin-6 production is controlled by glycogen synthase kinase-3 and STAT3 in the brain
    Eleonore Beurel
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294 0017, USA
    J Neuroinflammation 6:9. 2009
    ..To identify potential targets to control brain IL-6, we tested if IL-6 produced by glia is regulated by signal transducer and activator of transcription-3 (STAT3) and glycogen synthase kinase-3 (GSK3)...