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Open Access Highly Accessed Research article

GT1b-induced neurotoxicity is mediated by the Akt/GSK-3/tau signaling pathway but not caspase-3 in mesencephalic dopaminergic neurons

Eun S Chung1, Eugene Bok123, Sunghyang Sohn4, Young D Lee5, Hyung H Baik12 and Byung K Jin12*

  • * Corresponding author: Byung K Jin bkjin@khu.ac.kr

  • † Equal contributors

Author Affiliations

1 Department of Biochemistry and Molecular Biology, School of Medicine Kyung Hee University, Seoul 130-701, Korea

2 Neurodegeneration Control Research Center, Age-related and Brain Diseases Research Center, School of Medicine Kyung Hee University, Seoul 130-701, Korea

3 Brain Disease Research Center, Neuroscience Graduate Program, Division of Cell Transformation and Restoration, Department of Pharmacology, Ajou University School of Medicine, Suwon, 442-721, Korea

4 Laboratory Cell Biology, Institute for Medical Sciences, Ajou University School of Medicine, Suwon, 442-721, Korea

5 Department of Anatomy, Ajou University School of Medicine, Suwon, 442-721, Korea

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BMC Neuroscience 2010, 11:74  doi:10.1186/1471-2202-11-74

Published: 12 June 2010

Abstract

Background

Gangliosides, sialic acid-containing glycosphingolipids exist in mammalian cell membranes particularly neuronal membranes. The trisialoganglioside (GT1b) is one of the major brain gangliosides and acts as an endogenous regulator in the brain. We previously showed GT1b induces mesencephalic dopaminergic (DA) neuronal death, both in vivo and in vitro. We further investigate the underlying mechanisms of GT1b neurotoxicity.

Results

Consistent with earlier findings, GT1b attenuated the DA neuron number and dopamine uptake level in mesencephalic cultures. Morphological evidence revealed GT1b-induced chromatin condensation and nuclear fragmentation as well as an increased number of TUNEL-positive cells, compared to control cultures. Interestingly, while GT1b enhanced caspase-3 activity, DEVD, a caspase-3 inhibitor, failed to rescue DA neuronal death. Immunoblot analysis revealed that GT1b inactivates Akt through dephosphorylation at both Ser473 and Thr308, subsequent dephosphorylation of GSK-3β, a substrate of Akt, and hyperphosphorylation of tau, downstream of GSK-3β. Moreover, a GSK-3β specific inhibitor, L803-mt, attenuated tau phosphorylation and rescued DA neurons from cell death in mesencephalic cultures.

Conclusion

Our data provide novel evidence that a Akt/GSK-3β/tau-dependent, but not caspase-3 signaling pathway plays a pivotal role in GT1b-mediated neurotoxic actions on mesencephalic DA neurons.