Differential regulation of AKT, MAPK and GSK3β during C2-ceramide-induced neuronal death.
Evidence has implicated apoptosis as a mechanism underlying cell demise in diverse neurodegenerative diseases including Parkinson's disease (PD). Endogenous toxins and other stress signals activate the sphingomyelin pathway increasing the levels of ceramide, an important regulator of cell death. In the present paper we have analysed the contribution of PI3K/AKT-GSK3β and MAPK (ERK and JNK) pathways to cell death in a catecholaminergic cell line following exposure to C(2)-ceramide. We also explored the potential neuroprotective action of insulin-like growth factor-1 (IGF-1) and neurotrophin-3 (NT3). We demonstrated that C(2)-ceramide-induced cell death is associated to an early decrease in phosphorylation (inhibition) of PI3K/AKT and ERK, followed by phosphorylation (activation) of JNK and de-phosphorylation (activation) of glycogen synthase kinase-3 beta (GSK3β). NT3 and IGF-1 increased survival at early time points, but only IGF-1 is capable to attenuate C(2)-ceramide-mediated neuronal death, and this neuroprotection is associated to strong and permanent activation of AKT and inhibition of GSK3β. In conclusion, C(2)-ceramide initiates a series of events including an early inactivation of PI3K/AKT and ERK pathways followed by activation of JNK and activation of GSK3β and neuronal death, changes that are counteracted by IGF-1.
Arboleda
Gonzalo
G
Grupo de Neurociencias, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, Colombia. gharboledab@unal.edu.co
Cárdenas
Yolanda
Y
Rodríguez
Yeldy
Y
Morales
Luis Carlos
LC
Matheus
Luisa
L
Arboleda
Humberto
H
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism* / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism* / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000633:toxicity
C064769:N-acetylsphingosine; D018696:Neuroprotective Agents; D007334:Insulin-Like Growth Factor I; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D013110:Sphingosine