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Mol Neurobiol. 2016 Sep;53(7):4438-48. doi: 10.1007/s12035-015-9360-6. Epub 2015 Aug 7.

Domain-Specific Activation of Death-Associated Intracellular Signalling Cascades by the Cellular Prion Protein in Neuroblastoma Cells.

Vilches S1,2, Vergara C1,2,3, Nicolás O1,2,3, Mata Á1,2,3, Del Río JA4,5,6, Gavín R7,8,9.

Author information

1
Molecular and Cellular Neurobiotechnology, Barcelona Science Park, Institute for Bioengineering of Catalonia (IBEC), Parc Científic de Catalunya, Baldiri Reixac 15-21, 08028, Barcelona, Spain.
2
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
3
Department of Cell Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain.
4
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.
5
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. jadelrio@ibecbacelona.eu.
6
Department of Cell Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain. jadelrio@ibecbacelona.eu.
7
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.
8
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. rgavin@ub.edu.
9
Department of Cell Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain. rgavin@ub.edu.

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.

KEYWORDS:

Cellular prion protein; Neurotoxicity; Truncated prion protein

PMID:
26250617
DOI:
10.1007/s12035-015-9360-6
[Indexed for MEDLINE]

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