title: In vivo and in vitro neurotoxicity of the human prion protein (PrP) fragment P118-135 independently of PrP expression.
abstract: We recently demonstrated that the 118-135 putative transmembrane domain of prion protein (PrP) exhibited membrane fusogenic properties and induced apoptotic neuronal cell death of rat cortical neurons, independently of its aggregation state. The aim of the present study was to analyze the in vivo neurotoxicity of the prion fragment P118-135 and to evaluate the potential role of the physiological isoform of PrP in the P118-135-induced cell death. Here, we demonstrate that the nonfibrillar P118-135 is cytotoxic to retinal neurons in vivo as monitored by intravitreal inoculation and recording of the electrical activity of retina and tissue examination. Moreover, knock-out PrP gene mice exhibit similar sensitivity to the nonfibrillar P118-135-induced cell death and electrical perturbations, strongly suggesting that cell death occurs independently of PrP expression. Interestingly, a variant nonfusogenic P118-135 peptide (termed P118-135theta) had no effects on in vivo neuronal viability, suggesting that the P118-135-induced cell death is mediated by its membrane destabilizing properties. These data have further been confirmed in vitro. We show that the fusogenic peptide P118-135 induces death of cultured neurons from both wild-type and knock-out PrP gene mice via an apoptotic-mediated pathway, involving early caspase activation and DNA fragmentation. Altogether these results emphasize the neurotoxicity of the fusogenic nonfibrillar PrP transmembrane domain and indicate that fibril formation and PrP expression are not obligatory requirements for neuronal cell death. The use of synthetic prion peptides could provide insights into the understanding of neuronal loss mechanisms that take place during the development of the various types of spongiform encephalopathies.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Unité Mixte de Recherche 6097, Centre National de la Recherche Scientifique, 06560 Valbonne, France. chabry@ipmc.cnrs.fr
authors.forename: Joëlle
authors.initials: J
authors.lastname: Chabry
authors.forename: Christiane
authors.initials: C
authors.lastname: Ratsimanohatra
authors.forename: Isabelle
authors.initials: I
authors.lastname: Sponne
authors.forename: Pierre-Paul
authors.initials: PP
authors.lastname: Elena
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Vincent
authors.forename: Thierry
authors.initials: T
authors.lastname: Pillot
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D053938:DNA Fragmentation; D004333:Drug Administration Routes; D004596:Electroretinography / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D008561:Membrane Fusion / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000633:toxicity*; D017096:Prion Diseases / Q000209:etiology; D011328:Prions / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics / Q000633:toxicity*; D020033:Protein Isoforms / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D012160:Retina / Q000166:cytology / Q000187:drug effects
chemical_list: D010446:Peptide Fragments; D011328:Prions; D020033:Protein Isoforms; C417023:prion protein (118-135); D020169:Caspases