title: Oxidative stress activates the c-Abl/p73 proapoptotic pathway in Niemann-Pick type C neurons.
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.
authors.affiliation: Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Andres
authors.initials: A
authors.lastname: Klein
authors.forename: Carola
authors.initials: C
authors.lastname: Maldonado
authors.forename: Lina M
authors.initials: LM
authors.lastname: Vargas
authors.forename: Marcela
authors.initials: M
authors.lastname: Gonzalez
authors.forename: Fermín
authors.initials: F
authors.lastname: Robledo
authors.forename: Karen
authors.initials: K
authors.lastname: Perez de Arce
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Muñoz
authors.forename: Claudio
authors.initials: C
authors.lastname: Hetz
authors.forename: Alejandra R
authors.initials: AR
authors.lastname: Alvarez
authors.forename: Silvana
authors.initials: S
authors.lastname: Zanlungo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D052556:Niemann-Pick Disease, Type C / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D016315:Proto-Oncogene Proteins c-abl