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Oxidative stress activates the c-Abl/p73 proapoptotic pathway in Niemann-Pick type C neurons

2010; Elsevier BV; Volume: 41; Issue: 1 Linguagem: Inglês

10.1016/j.nbd.2010.09.008

1095-953X

Andrés D. Klein, Carola Maldonado, Lina Moitoso de Vargas, Marcela González, Fermín Robledo, Karen Perez de Arce, Francisco J. Muñoz, Claudio Hetz, Alejandra Álvarez, Silvana Zanlungo,

Calcium signaling and nucleotide metabolism

Niemann-Pick type C (NPC) is a neurodegenerative disease characterized by the intralysosomal accumulation of cholesterol leading to neuronal apoptosis. We have previously reported the activation of the c-Abl/p73 proapoptotic pathway in the cerebellum of NPC mice; however, upstream signals underlying the engagement of this pathway remain unknown. Here, we investigate the possible role of oxidative stress in the activation of c-Abl/p73 using different in vitro and in vivo NPC models. Our results indicate a close temporal correlation between the appearance of nitrotyrosine (N-Tyr; a post-translational tyrosine modification caused by oxidative stress) and the activation of c-Abl/p73 in NPC models. To test the functional role of oxidative stress in NPC, we have treated NPC neurons with the antioxidant NAC and observed a dramatic decrease of c-Abl/p73 activation and a reduction in the levels of apoptosis in NPC models. In conclusion, our data suggest that oxidative stress is the main upstream stimulus activating the c-Abl/p73 pathway and neuronal apoptosis in NPC neurons.