ABSTRACT
The role of p53 in neurodegenerative diseases is essentially associated with neuronal death. Recently an alternative point of view is emerging, as altered p53 conformation and impaired protein function have been found in fibroblasts and blood cells derived from Alzheimer's disease patients. Here, using stable transfected SH-SY5Y cells overexpressing APP751wt (SY5Y-APP) we demonstrated that the expression of an unfolded p53 conformation compromised neuronal functionality. In particular, these cells showed (i) augmented expression of amyloid precursor protein (APP) and its metabolites, including the C-terminal fragments C99 and C83 and ß-amyloid peptide (ii) high levels of oxidative markers, such as 4-hydroxy-2-nonenal Michael-adducts and 3-nitro-tyrosine and (iii) altered p53 conformation, mainly due to nitration of its tyrosine residues. The consequences of high-unfolded p53 expression resulted in loss of p53 pro-apoptotic activity, and reduction of growth-associated protein 43 (GAP-43) mRNA and protein levels. The role of unfolded p53 in cell death resistance and lack of GAP-43 transcription was demonstrated by ZnCl(2) treatment. Zinc supplementation reverted p53 wild-type tertiary structure, increased cells sensitivity to acute cytotoxic injury and GAP-43 levels in SY5Y-APP clone.
Subject(s)
GAP-43 Protein/metabolism , Neurons/metabolism , Tumor Suppressor Protein p53/chemistry , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Chlorides/pharmacology , GAP-43 Protein/genetics , Humans , Hydrogen Peroxide/toxicity , Oxidative Stress , Protein Structure, Tertiary , Protein Unfolding , RNA, Messenger/metabolism , Transcription, Genetic/drug effects , Tumor Suppressor Protein p53/metabolism , Tyrosine/analogs & derivatives , Tyrosine/chemistry , Zinc Compounds/pharmacologyABSTRACT
In 2008, academic researchers and public service officials created a university extension studies platform based on online and on-site meetings denominated "Work-Related Accidents Forum: Analysis, Prevention, and Other Relevant Aspects. Its aim was to help public agents and social partners to propagate a systemic approach that would be helpful in the surveillance and prevention of work-related accidents. This article describes and analyses such a platform. Online access is free and structured to: support dissemination of updated concepts; support on-site meetings and capacity to build educational activities; and keep a permanent space for debate among the registered participants. The desired result is the propagation of a social-technical-systemic view of work-related accidents that replaces the current traditional view that emphasizes human error and results in blaming the victims. The Forum uses an educational approach known as permanent health education, which is based on the experience and needs of workers and encourages debate among participants. The forum adopts a problematizing pedagogy that starts from the requirements and experiences of the social actors and stimulates support and discussions among them in line with an ongoing health educational approach. The current challenge is to turn the platform into a social networking website in order to broaden its links with society.
