title: Domain-Specific Activation of Death-Associated Intracellular Signalling Cascades by the Cellular Prion Protein in Neuroblastoma Cells.
abstract: The biological functions of the cellular prion protein remain poorly understood. In fact, numerous studies have aimed to determine specific functions for the different protein domains. Studies of cellular prion protein (PrP(C)) domains through in vivo expression of molecules carrying internal deletions in a mouse Prnp null background have provided helpful data on the implication of the protein in signalling cascades in affected neurons. Nevertheless, understanding of the mechanisms underlying the neurotoxicity induced by these PrP(C) deleted forms is far from complete. To better define the neurotoxic or neuroprotective potential of PrP(C) N-terminal domains, and to overcome the heterogeneity of results due to the lack of a standardized model, we used neuroblastoma cells to analyse the effects of overexpressing PrP(C) deleted forms. Results indicate that PrP(C) N-terminal deleted forms were properly processed through the secretory pathway. However, PrPΔF35 and PrPΔCD mutants led to death by different mechanisms sharing loss of alpha-cleavage and activation of caspase-3. Our data suggest that both gain-of-function and loss-of-function pathogenic mechanisms may be associated with N-terminal domains and may therefore contribute to neurotoxicity in prion disease. Dissecting the molecular response induced by PrPΔF35 may be the key to unravelling the physiological and pathological functions of the prion protein.
authors.affiliation: Molecular and Cellular Neurobiotechnology, Barcelona Science Park, Institute for Bioengineering of Catalonia (IBEC), Parc Científic de Catalunya, Baldiri Reixac 15-21, 08028, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Vilches
authors.affiliation: Molecular and Cellular Neurobiotechnology, Barcelona Science Park, Institute for Bioengineering of Catalonia (IBEC), Parc Científic de Catalunya, Baldiri Reixac 15-21, 08028, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Department of Cell Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Vergara
authors.affiliation: Molecular and Cellular Neurobiotechnology, Barcelona Science Park, Institute for Bioengineering of Catalonia (IBEC), Parc Científic de Catalunya, Baldiri Reixac 15-21, 08028, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Department of Cell Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Nicolás
authors.affiliation: Molecular and Cellular Neurobiotechnology, Barcelona Science Park, Institute for Bioengineering of Catalonia (IBEC), Parc Científic de Catalunya, Baldiri Reixac 15-21, 08028, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Department of Cell Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Ágata
authors.initials: Á
authors.lastname: Mata
authors.affiliation: Molecular and Cellular Neurobiotechnology, Barcelona Science Park, Institute for Bioengineering of Catalonia (IBEC), Parc Científic de Catalunya, Baldiri Reixac 15-21, 08028, Barcelona, Spain. jadelrio@ibecbacelona.eu.|Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. jadelrio@ibecbacelona.eu.|Department of Cell Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain. jadelrio@ibecbacelona.eu.
authors.forename: José A
authors.initials: JA
authors.lastname: Del Río
authors.affiliation: Molecular and Cellular Neurobiotechnology, Barcelona Science Park, Institute for Bioengineering of Catalonia (IBEC), Parc Científic de Catalunya, Baldiri Reixac 15-21, 08028, Barcelona, Spain. rgavin@ub.edu.|Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. rgavin@ub.edu.|Department of Cell Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain. rgavin@ub.edu.
authors.forename: Rosalina
authors.initials: R
authors.lastname: Gavín
mesh_terms: D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D053418:Death Domain Receptor Signaling Adaptor Proteins; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / Q000378:metabolism; D000072002:Prion Proteins / Q000378:metabolism*; D014162:Transfection
chemical_list: D053418:Death Domain Receptor Signaling Adaptor Proteins; D000072002:Prion Proteins; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
keywords: Cellular prion protein; Neurotoxicity; Truncated prion protein