ToxSci Advance Access first published online on March 6, 2007
This version published online on April 5, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm040
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Inhibition of paraquat-induced autophagy accelerates the apoptotic cell death in neuroblastoma SH-SY5Y cells
1 CIBER de Enfermedades Neurodegenerativas (CIBERNED). Departamento de Bioquímica y Biología Molecular y Genética, E.U. Enfermería y T.O., Universidad de Extremadura, Cáceres, Spain 2 Departamento de Química Orgánica, Facultad de Veterinaria, Universidad de Extremadura, Cáceres, Spain 3 Departamento de Biología Celular, Facultad de Veterinaria, Universidad de Extremadura, Cáceres, Spain 4 Departamento de Medicina y Sanidad Animal, Facultad de Veterinaria, Universidad de Extremadura, Cáceres, Spain
* Address correspondence to: Rosa-Ana González-Polo. CIBER de Enfermedades Neurodegenerativas.(CIBERNED). Departamento de Bioquimica y Biologia Molecular y Genética. E.U. Enfermeria y Terapia Ocupacional. Universidad de Extremadura. Avda. Universidad s/n 10071 Cáceres, Spain. Phone: 34-927-257450. Fax: 34-927-257451. e-mail: rosapolo{at}unex.es
Received January 12, 2007; revision received February 27, 2007; accepted February 27, 2007
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Abstract |
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Autophagy is a degradative mechanism involved in the recycling and turnover of cytoplasmic constituents from eukaryotic cells. This phenomenon of autophagy has been observed in neurons from patients with Parkinson's disease, suggesting a functional role for autophagy in neuronal cell death. On the other hand, it has been demonstrated that exposure to pesticides can be a risk factor in the incidence of Parkinson's disease. In this sense, paraquat (1, 1'-dimethyl-4, 4'-bipyridinium dichloride), a widely used herbicide that is structurally similar to the known dopaminergic neurotoxicant MPP+ (1-methyl-4-phenyl-pyridine), has been suggested as a potential etiologic factor for the development of Parkinson's disease. The current study shows, for the first time, that low concentrations of paraquat induce several characteristic of autophagy in human neuroblastoma SH-SY5Y cells. In this way, paraquat induced the accumulation of autophagic vacuoles in the cytoplasm and the recruitment of a LC3-GFP fusion protein to autophagic vacuoles. Furthermore, the cells treated with paraquat showed an increased of the long-lived proteins degradation which is blocked in the presence of the autophagy inhibitor 3-methyladenine and regulated by the mammalian target of rapamycin (mTOR) signalling. Finally, the cells succumbed to cell death with hallmarks of apoptosis such as phosphatidylserine exposure, caspase activation and chromatin condensation. While caspase inhibition retarded cell death, autophagy inhibition accelerated the apoptotic cell death induced by paraquat. Altogether, these findings show the relationship between autophagy and apoptotic cell death in human neuroblastoma cells treated with paraquat.
Key Words: Paraquat; vacuoles; apoptosis; Parkinson.
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