RESUMO
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-GSK3ß 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 (GSK3ß). 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 GSK3ß. 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 GSK3ß and neuronal death, changes that are counteracted by IGF-1.
Assuntos
Quinase 3 da Glicogênio Sintase/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Esfingosina/análogos & derivados , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Quinase 3 da Glicogênio Sintase/fisiologia , Glicogênio Sintase Quinase 3 beta , Fator de Crescimento Insulin-Like I/farmacologia , Fator de Crescimento Insulin-Like I/fisiologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Esfingosina/toxicidadeRESUMO
The Wiedemann-Rautenstrauch syndrome (WRS, OMIM: 264090) characterizes a premature aging syndrome in which several features of aging are apparent at birth. We did not find mutations in Lamin A/C (LMNA) gene in four WRS patients, and in particular, we did not find the G608G mutation (GGC > GGT transition) which is associated with most cases with Hutchinson-Gilford progeria (OMIM 176670). These findings suggest that WRS represents a distinct progeroid entity that may be caused by recessive mutations of a different gene.