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

Abstract

BackgroundGangliosides, 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.ResultsConsistent 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.ConclusionOur 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.

Vitamin K Deficiency Induced by Warfarin Is Associated With Cognitive and Behavioral Perturbations, and Alterations in Brain Sphingolipids in Rats

“…Microglial activation was subsequently shown to be mediated by protein kinase C and NADPH oxidase ( Min et al, 2004 ). Ganglioside GT1b has also been found to be neurotoxic to dopaminergic neurons in vitro ( Chung et al, 2001 ) through a modulation of the Akt/GSK-3/Tau signaling pathway ( Chung et al, 2010 ). In vivo , injection of GT1b into the substantia nigra resulted in the death of nigral neurons, a finding associated with activation of microglia ( Ryu et al, 2002 ).…”

Dodging the bullet: therapeutic resistance mechanisms in pediatric cancers

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Selenium treatment significantly inhibits tumor necrosis factor-α-induced cell death and tau hyperphosphorylation in neuroblastoma cells

“…The tau protein is a phosphoprotein that potentially has 80 serine/threonine and 5 tyrosine phosphorylation sites (15). Phosphorylation of tau was shown to be regulated by kinases, such as GSK-3β and Akt (15,16). To determine whether selenite treatment is accompanied by downregulation of the activity of these kinases, the phosphorylation level of GSK-3β and Akt was measured.…”