PrP(106-126) activates neuronal intracellular kinases and Egr1 synthesis through activation of NADPH-oxidase independently of PrPc.
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.
Gavín
Rosalina
R
Development and Regeneration of the CNS, Department of Cell Biology, Barcelona Science Park - IRB, University of Barcelona, Spain.
Braun
Nathalie
N
Nicolas
Oriol
O
Parra
Beatriz
B
Ureña
Jesus Mariano
JM
Mingorance
Ana
A
Soriano
Eduardo
E
Torres
Juan María
JM
Aguzzi
Adriano
A
del Río
José Antonio
JA
D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D051766:Early Growth Response Protein 1; D004789:Enzyme Activation; D005260:Female; D038341:Glycogen Synthase Kinases / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000096:biosynthesis*; D007150:Immunohistochemistry; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology*; D010446:Peptide Fragments / Q000502:physiology*; D018621:PrPC Proteins / Q000502:physiology*; D011247:Pregnancy; D011328:Prions / Q000502:physiology*; D017382:Reactive Oxygen Species; D014157:Transcription Factors / Q000096:biosynthesis*; D016875:tau Proteins / Q000378:metabolism
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D010446:Peptide Fragments; D018621:PrPC Proteins; D011328:Prions; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C082632:prion protein (106-126); D016875:tau Proteins; D019255:NADPH Oxidases; D038341:Glycogen Synthase Kinases; D020928:Mitogen-Activated Protein Kinases