Skip to main content
Article thumbnail
Location of Repository

Involvment of Cytosolic and Mitochondrial GSK-3β in Mitochondrial Dysfunction and Neuronal Cell Death of MPTP/MPP+-Treated Neurons

By Agnès Petit-Paitel, Frédéric Brau, Julie Cazareth and Joëlle Chabry


Aberrant mitochondrial function appears to play a central role in dopaminergic neuronal loss in Parkinson's disease (PD). 1-methyl-4-phenylpyridinium iodide (MPP+), the active metabolite of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is a selective inhibitor of mitochondrial complex I and is widely used in rodent and cell models to elicit neurochemical alterations associated with PD. Recent findings suggest that Glycogen Synthase Kinase-3β (GSK-3β), a critical activator of neuronal apoptosis, is involved in the dopaminergic cell death. In this study, the role of GSK-3β in modulating MPP+-induced mitochondrial dysfunction and neuronal death was examined in vivo, and in two neuronal cell models namely primary cultured and immortalized neurons. In both cell models, MPTP/MPP+ treatment caused cell death associated with time- and concentration-dependent activation of GSK-3β, evidenced by the increased level of the active form of the kinase, i.e. GSK-3β phosphorylated at tyrosine 216 residue. Using immunocytochemistry and subcellular fractionation techniques, we showed that GSK-3β partially localized within mitochondria in both neuronal cell models. Moreover, MPP+ treatment induced a significant decrease of the specific phospho-Tyr216-GSK-3β labeling in mitochondria concomitantly with an increase into the cytosol. Using two distinct fluorescent probes, we showed that MPP+ induced cell death through the depolarization of mitochondrial membrane potential. Inhibition of GSK-3β activity using well-characterized inhibitors, LiCl and kenpaullone, and RNA interference, prevented MPP+-induced cell death by blocking mitochondrial membrane potential changes and subsequent caspase-9 and -3 activation. These results indicate that GSK-3β is a critical mediator of MPTP/MPP+-induced neurotoxicity through its ability to regulate mitochondrial functions. Inhibition of GSK-3β activity might provide protection against mitochondrial stress-induced cell death

Topics: Research Article
Publisher: Public Library of Science
OAI identifier:
Provided by: PubMed Central

Suggested articles


  1. (2004). 1-Azakenpaullone is a selective inhibitor of glycogen synthase kinase-3 beta.
  2. (1989). Abnormalities of the electron transport chain in idiopathic Parkinson’s disease.
  3. (2006). Bradykinin prevents reperfusion injury by targeting mitochondrial permeability transition pore through glycogen synthase kinase 3beta.
  4. (2008). Cardioprotective effect of morphine and a blocker of glycogen synthase kinase 3 beta, SB216763 [3-(2,4-dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole2,5-dione], via inhibition of the mitochondrial permeability transition pore.
  5. (2001). Caspase-3 activation induced by inhibition of mitochondrial complex I is facilitated by glycogen synthase kinase-3beta and attenuated by lithium.
  6. (2007). Caspasedependent apoptosis induced by thapsigargin was prevented by glycogen synthase kinase-3 inhibitors in cultured rat cortical neurons.
  7. (1998). Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-D-aspartate receptor-mediated calcium influx.
  8. (2005). Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage.
  9. (2001). Conformational change of Bax: a question of life or death.
  10. (2006). Cytoprotection by lithium and valproate varies between cell types and cellular stresses.
  11. (1989). Deficiencies in complex I subunits of the respiratory chain in Parkinson’s disease.
  12. (1995). Different localization of tau protein kinase I/glycogen synthase kinase-3 beta from glycogen synthase kinase-3 alpha in cerebellum mitochondria.
  13. (2004). Emerging experimental therapeutics for bipolar disorder: insights from the molecular and cellular actions of current mood stabilizers.
  14. (2006). Epidemiology of Parkinson’s disease.
  15. (2007). Erythropoietin prevents PC12 cells from 1-methyl-4-phenylpyridinium ion-induced apoptosis via the Akt/ GSK-3beta/caspase-3 mediated signaling pathway.
  16. (2009). Ethanol prevents oxidant-induced mitochondrial permeability transition pore opening in cardiac cells.
  17. (2002). Glycogen synthase kinase 3 (GSK-3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation.
  18. (2008). Glycogen synthase kinase 3 inhibition slows mitochondrial adenine nucleotide transport and regulates voltage-dependent anion channel phosphorylation.
  19. (2004). Glycogen synthase kinase 3beta (GSK3beta) mediates 6-hydroxydopamine-induced neuronal death.
  20. (2003). Glycogen synthase kinase-3 beta is highly activated in nuclei and mitochondria.
  21. (1980). Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase.
  22. (2004). Glycogen synthase kinase-3 inhibitors prevent caspase-dependent apoptosis induced by ethanol in cultured rat cortical neurons.
  23. (2006). Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1.
  24. (2003). Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the actions of p53.
  25. (2007). Glycogen synthase kinase-3beta activity plays very important roles in determining the fate of oxidative stress-inflicted neuronal cells.
  26. (2000). Glycogen synthase kinase-3beta facilitates staurosporine- and heat shock-induced apoptosis. Protection by lithium.
  27. (2007). Glycogen synthase kinase-3beta induces neuronal cell death via direct phosphorylation of mixed lineage kinase 3.
  28. (2004). Glycogen synthase kinase-3beta phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis.
  29. (2008). Glycogen synthase kinase-3beta, or a link between amyloid and tau pathology?
  30. (2008). Grundke-Iqbal I
  31. (2007). GSK-3 inhibitors for Alzheimer’s disease.
  32. (2003). GSK-3: tricks of the trade for a multi-tasking kinase.
  33. (2004). In vivo regulation of glycogen synthase kinase-3beta (GSK3beta) by serotonergic activity in mouse brain.
  34. (2005). Inhibition of glycogen synthase kinase-3 protects cells from intrinsic but not extrinsic oxidative stress.
  35. (2007). Inhibition of glycogen synthase kinase-3beta protects dopaminergic neurons from MPTP toxicity.
  36. (2008). Inhibition of GSK3beta by postconditioning is required to prevent opening of the mitochondrial permeability transition pore during reperfusion.
  37. (2005). Isoflurane postconditioning prevents opening of the mitochondrial permeability transition pore through inhibition of glycogen synthase kinase 3beta.
  38. (2004). Lithium neuroprotection: molecular mechanisms and clinical implications. Expert Rev Mol Med 6: 1–18. GSK-3b and
  39. (1998). Lithium protects rat cerebellar granule cells against apoptosis induced by anticonvulsants, phenytoin and carbamazepine.
  40. (1999). Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity.
  41. (2007). Mechanistic insights into diabetes mellitus and oxidative stress.
  42. (2008). Mitochondria in the aetiology and pathogenesis of Parkinson’s disease.
  43. (2005). Mitochondria take center stage in aging and neurodegeneration.
  44. (1989). Mitochondrial complex I deficiency in Parkinson’s disease.
  45. (2003). Models of Parkinson’s disease. Mov Disord 18: 729–737. GSK-3b and Mitochondria PLoS
  46. (1999). Modulation of CNS signal transduction pathways and gene expression by moodstabilizing agents: therapeutic implications.
  47. (2007). Modulation of the mitochondrial permeability transition pore complex in GSK-3beta-mediated myocardial protection.
  48. (2004). MPTP as a mitochondrial neurotoxic model of Parkinson’s disease.
  49. (2002). Neuroprotective effects of lithium in cultured cells and animal models of diseases.
  50. (2007). Nonpsychoactive cannabidiol prevents prion accumulation and protects neurons against prion toxicity.
  51. (1996). Origin and functional consequences of the complex I defect in Parkinson’s disease.
  52. (2006). Parkinson’s disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled.
  53. (2003). Parkinson’s disease: mechanisms and models.
  54. (2002). PKC, MAP kinases and the bcl-2 family of proteins as long-term targets for mood stabilizers.
  55. (2004). Prevention of MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) dopaminergic neurotoxicity in mice by chronic lithium: involvements of Bcl-2 and Bax.
  56. (2001). Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3 beta.
  57. (2007). Protocol for the MPTP mouse model of Parkinson’s disease.
  58. (2003). Rapid accumulation of Akt in mitochondria following phosphatidylinositol 3-kinase activation.
  59. (2000). Role of glycogen synthase kinase-3beta in neuronal apoptosis induced by trophic withdrawal.
  60. (2008). Ser9 phosphorylation of mitochondrial GSK-3beta is a primary mechanism of cardiomyocyte protection by erythropoietin against oxidant-induced apoptosis.
  61. (2004). Short-term lithium treatment promotes neuronal survival and proliferation in rat striatum infused with quinolinic acid, an excitotoxic model of Huntington’s disease.
  62. (2008). Synergistic neuroprotective effects of lithium and valproic acid or other histone deacetylase inhibitors in neurons: roles of glycogen synthase kinase-3 inhibition.
  63. (2003). Targeting programmed cell death in neurodegenerative diseases.
  64. (2004). The glamour and gloom of glycogen synthase kinase-3.
  65. (2002). The insulin signalling pathway.
  66. (2001). The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling.
  67. (2006). The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways.
  68. (2001). The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a technical review of its utility and safety.
  69. (2004). Wnt-3a overcomes beta-amyloid toxicity in rat hippocampal neurons.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.