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.
Highlights
Gangliosides, sialic acid-containing glycosphingolipids exist in mammalian cell membranes neuronal membranes
We demonstrate for the first time that trisialoganglioside 1b (GT1b) neurotoxicity is accompanied by inactivation of Akt, activation of glycogen synthase kinase 3 (GSK-3β) and increase in tau phosphorylation in mesencephalic DA neurons, both in vivo and in vitro
Additional immunostaining was performed with a neuron specific nuclear protein (NeuN) antibody for general neurons and GABA antibody for GABAergic neurons (Figure 1D)
Summary
Gangliosides, sialic acid-containing glycosphingolipids exist in mammalian cell membranes neuronal membranes. In vivo and in vitro models of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl-4-phenylpyridinium (MPP+) or 6-hydroxydopamine (6-OHDA) reveal that apoptosis is the principal mechanism underlying neuronal death [1,2,3,4]. Gangliosides localized to neurofibrillary tangles (senile plaques) in brain tissue of Alzheimer's disease (AD) patients and Betz cells of precentral gyrus in amyotrophic lateral sclerosis patients [18,19]. These findings support the possibility that under pathological conditions, gangliosides serve as cytotoxic factors in the central nervous system (CNS)
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