The alpha-secretase-derived N-terminal product of cellular prion, N1, displays neuroprotective function in vitro and in vivo.
Cellular prion protein (PrP(c)) undergoes a disintegrin-mediated physiological cleavage, generating a soluble amino-terminal fragment (N1), the function of which remained unknown. Recombinant N1 inhibits staurosporine-induced caspase-3 activation by modulating p53 transcription and activity, whereas the PrP(c)-derived pathological fragment (N2) remains biologically inert. Furthermore, N1 protects retinal ganglion cells from hypoxia-induced apoptosis, reduces the number of terminal deoxynucleotidyltransferase-mediated biotinylated UTP nick end labeling-positive and p53-immunoreactive neurons in a pressure-induced ischemia model of the rat retina and triggers a partial recovery of b-waves but not a-waves of rat electroretinograms. Our work is the first demonstration that the alpha-secretase-derived PrP(c) fragment N1, but not N2, displays in vivo and in vitro neuroprotective function by modulating p53 pathway. It further demonstrates that distinct N-terminal cleavage products of PrP(c) harbor different biological activities underlying the various phenotypes linking PrP(c) to cell survival.
Guillot-Sestier
Marie-Victoire
MV
Institut de Pharmacologie Moléculaire et Cellulaire and Institut de Neuromédecine Moléculaire, UMR6097 CNRS/UNSA, Equipe Labellisée Fondation pour la Recherche Médicale, 660 Route des Lucioles, Sophia-Antipolis, 06560 Valbonne, France.
Sunyach
Claire
C
Druon
Charlotte
C
Scarzello
Sabine
S
Checler
Frédéric
F
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D018621:PrPC Proteins; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; C505409:Casp3 protein, mouse; D053148:Caspase 3; D019311:Staurosporine