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

Klein Posternack, Andrés David; Maldonado Vera, Carola Patricia; Vargas Rojas, Lina Marcela; González Bustos, Marcela Paz; Robledo Plaza, Fermín Alberto; Pérez de Arce Guzman, Karen Andrea; Muñoz, Francisco J.; Hetz, Claudio; Álvarez, Alejandra R.; Zanlungo Matsuhiro, Silvana

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

Date

2010

Authors

Klein Posternack, Andrés David

Maldonado Vera, Carola Patricia

Vargas Rojas, Lina Marcela

González Bustos, Marcela Paz

Robledo Plaza, Fermín Alberto

Pérez de Arce Guzman, Karen Andrea

Muñoz, Francisco J.

Hetz, Claudio

Álvarez, Alejandra R.

Zanlungo Matsuhiro, Silvana

Abstract

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.