title: Overstimulation of PrPC signaling pathways by prion peptide 106-126 causes oxidative injury of bioaminergic neuronal cells.
abstract: Transmissible spongiform encephalopathies, also called prion diseases, are characterized by neuronal loss linked to the accumulation of PrP(Sc), a pathologic variant of the cellular prion protein (PrP(C)). Although the molecular and cellular bases of PrP(Sc)-induced neuropathogenesis are not yet fully understood, increasing evidence supports the view that PrP(Sc) accumulation interferes with PrP(C) normal function(s) in neurons. In the present work, we exploit the properties of PrP-(106-126), a synthetic peptide encompassing residues 106-126 of PrP, to investigate into the mechanisms sustaining prion-associated neuronal damage. This peptide shares many physicochemical properties with PrP(Sc) and is neurotoxic in vitro and in vivo. We examined the impact of PrP-(106-126) exposure on 1C11 neuroepithelial cells, their neuronal progenies, and GT1-7 hypothalamic cells. This peptide triggers reactive oxygen species overflow, mitogen-activated protein kinase (ERK1/2), and SAPK (p38 and JNK1/2) sustained activation, and apoptotic signals in 1C11-derived serotonergic and noradrenergic neuronal cells, while having no effect on 1C11 precursor and GT1-7 cells. The neurotoxic action of PrP-(106-126) relies on cell surface expression of PrP(C), recruitment of a PrP(C)-Caveolin-Fyn signaling platform, and overstimulation of NADPH-oxidase activity. Altogether, these findings provide actual evidence that PrP-(106-126)-induced neuronal injury is caused by an amplification of PrP(C)-associated signaling responses, which notably promotes oxidative stress conditions. Distorsion of PrP(C) signaling in neuronal cells could hence represent a causal event in transmissible spongiform encephalopathy pathogenesis.
authors.affiliation: Différenciation Cellulaire et Prions, CNRS FRE2937, Institut André Lwoff, 7 rue Guy Môquet, 94801 Villejuif Cedex, France.
authors.forename: Mathéa
authors.initials: M
authors.lastname: Pietri
authors.forename: Andréa
authors.initials: A
authors.lastname: Caprini
authors.forename: Sophie
authors.initials: S
authors.lastname: Mouillet-Richard
authors.forename: Elodie
authors.initials: E
authors.lastname: Pradines
authors.forename: Myriam
authors.initials: M
authors.lastname: Ermonval
authors.forename: Jacques
authors.initials: J
authors.lastname: Grassi
authors.forename: Odile
authors.initials: O
authors.lastname: Kellermann
authors.forename: Benoit
authors.initials: B
authors.lastname: Schneider
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D008969:Molecular Sequence Data; D009249:NADP / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D010446:Peptide Fragments / Q000633:toxicity*; D018621:PrPC Proteins / Q000502:physiology*; D011328:Prions / Q000633:toxicity*; D051076:Proto-Oncogene Proteins c-fyn / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D010446:Peptide Fragments; D018621:PrPC Proteins; D011328:Prions; D017382:Reactive Oxygen Species; C082632:prion protein (106-126); D009249:NADP; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; D048049:Extracellular Signal-Regulated MAP Kinases; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione