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

Authors
Chung, ES; Bok, E; Sohn, S; Lee, YD; Baik, HH; Jin, BK
Citation
BMC neuroscience, 1174-74, 2010
Journal Title
BMC neuroscience
ISSN
1471-2202
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-3beta, a substrate of Akt, and hyperphosphorylation of tau, downstream of GSK-3beta. Moreover, a GSK-3beta 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-3beta/tau-dependent, but not caspase-3 signaling pathway plays a pivotal role in GT1b-mediated neurotoxic actions on mesencephalic DA neurons.
MeSH terms
Analysis of VarianceAnimalsApoptosis/drug effectsBlotting, WesternCaspase 3/metabolismCell CountCells, CulturedDopamine/*metabolismFemaleGangliosides/*pharmacologyGlycogen Synthase Kinase 3/*metabolismImmunohistochemistryIn Situ Nick-End LabelingMesencephalon/cytology/drug effects/*metabolismMicroscopy, ImmunoelectronNeurons/cytology/drug effects/*metabolismPhosphorylation/drug effectsProto-Oncogene Proteins c-akt/*metabolismRatsRats, Sprague-DawleySignal Transduction/*drug effectstau Proteins/*metabolism
DOI
10.1186/1471-2202-11-74
PMID
20540782
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Microbiology
Journal Papers > School of Medicine / Graduate School of Medicine > Anatomy
AJOU Authors
손, 성향이, 영돈
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