PrP(106–126) activates neuronal intracellular kinases and Egr1 synthesis through activation of NADPH‐oxidase independently of PrPc

Abstract

Prion diseases are characterised by severe neural lesions linked to the presence of an abnormal protease-resistant isoform of cellular prion protein (PrPc). The peptide PrP(106-126) is widely used as a model of neurotoxicity in prion diseases. Here, we examine in detail the intracellular signalling cascades induced by PrP(106-126) in cortical neurons and the participation of PrPc. We show that PrP(106-126) induces the activation of subsets of intracellular kinases (e.g., ERK1/2), early growth response 1 synthesis and induces caspase-3 activity, all of which are mediated by nicotinamide adenine dinucleotide phosphate hydrogen-oxidase activity and oxidative stress. However, cells lacking PrPc are similarly affected after peptide exposure, and this questions the involvement of PrPc in these effects.

Overstimulation of PrPC Signaling Pathways by Prion Peptide 106-126 Causes Oxidative Injury of Bioaminergic Neuronal Cells

“…These intracellular events are in agreement with observations in TSE-infected brains indicating hallmarks of oxidative stress (36,39) and enhanced levels of MAPK/SAPK (40). Several other in vitro studies carried out using the PrP-(106 -126) neurotoxic peptide also support our observations (25,(41)(42)(43). Here, however, the time schedule of the deleterious events observed in 1C11-derived neuronal cells contrasts with the long delay between PrP-(106 -126) exposure and cell response as recorded with other experimental systems (42)(43)(44).…”

“…Several other in vitro studies carried out using the PrP-(106 -126) neurotoxic peptide also support our observations (25,(41)(42)(43). Here, however, the time schedule of the deleterious events observed in 1C11-derived neuronal cells contrasts with the long delay between PrP-(106 -126) exposure and cell response as recorded with other experimental systems (42)(43)(44). Such a discrepancy may relate to the conditions of preparation of PrP-(106 -126), which influence the aggregation state of the peptide (45,46).…”

The Extracellular Regulated Kinase-1 (ERK1) Controls Regulated α-Secretase-mediated Processing, Promoter Transactivation, and mRNA Levels of the Cellular Prion Protein

“…In this case, the ERK-1-mediated production of N1 could be seen as a cellular response to counterbalance PrP c -mediated toxicity. This hypothesis seems to be supported by the observation that in cells overexpressing a PrP c construct lacking the 32-134 amino-terminal sequence (that encompasses most of the N1 domain), ERK phosphorylation is still stimulated but leads to cell death, oxidative injury, and neurodegeneration (62)(63)(64). This could be due to the fact that whereas N-terminal-truncated PrP c is increased, its neuroprotective counterpart N1 is lacking.…”

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

“…Furthermore, the transmembrane part of PrP c holds specific residues that regulate chain orientation when the protein is anchored to the cell membrane (Ott et al, 2007) promote neurotoxicity in neuronal cell cultures (Forloni et al, 1993) because of their self-aggregative properties. However, these studies are subject to debate since the requirement of PrP c expression for synthetic peptide toxicity is controversial (see for example (Brown, 2000;Fioriti et al, 2005;Gavin et al, 2005;Kunz et al, 1999;Singh et al, 2002)). N-terminally truncated constructions, like F35 or Dpl protein, lack residues 105-125 (Luhrs et al, 2003;Mo et al, 2001;Shmerling et al, 1998).…”