title: Disease-associated mutations in the prion protein impair laminin-induced process outgrowth and survival.
abstract: Prions, the agents of transmissible spongiform encephalopathies, require the expression of prion protein (PrP(C)) to propagate disease. PrP(C) is converted into an abnormal insoluble form, PrP(Sc), that gains neurotoxic activity. Conversely, clinical manifestations of prion disease may occur either before or in the absence of PrP(Sc) deposits, but the loss of normal PrP(C) function contribution for the etiology of these diseases is still debatable. Prion disease-associated mutations in PrP(C) represent one of the best models to understand the impact of PrP(C) loss-of-function. PrP(C) associates with various molecules and, in particular, the interaction of PrP(C) with laminin (Ln) modulates neuronal plasticity and memory formation. To assess the functional alterations associated with PrP(C) mutations, wild-type and mutated PrP(C) proteins were expressed in a neural cell line derived from a PrP(C)-null mouse. Treatment with the laminin γ1 chain peptide (Ln γ1), which mimics the Ln binding site for PrP(C), increased intracellular calcium in cells expressing wild-type PrP(C), whereas a significantly lower response was observed in cells expressing mutated PrP(C) molecules. The Ln γ1 did not promote process outgrowth or protect against staurosporine-induced cell death in cells expressing mutated PrP(C) molecules in contrast to cells expressing wild-type PrP(C). The co-expression of wild-type PrP(C) with mutated PrP(C) molecules was able to rescue the Ln protective effects, indicating the lack of negative dominance of PrP(C) mutated molecules. These results indicate that PrP(C) mutations impair process outgrowth and survival mediated by Ln γ1 peptide in neural cells, which may contribute to the pathogenesis of genetic prion diseases.
authors.affiliation: International Research Center, A. C. Camargo Hospital, and National Institute for Translational Neuroscience (CNPq/MCT/FAPESP), São Paulo 01508-010, Brazil.
authors.forename: Cleiton F
authors.initials: CF
authors.lastname: Machado
authors.forename: Flavio H
authors.initials: FH
authors.lastname: Beraldo
authors.forename: Tiago G
authors.initials: TG
authors.lastname: Santos
authors.forename: Dominique
authors.initials: D
authors.lastname: Bourgeon
authors.forename: Michele C
authors.initials: MC
authors.lastname: Landemberger
authors.forename: Martin
authors.initials: M
authors.lastname: Roffé
authors.forename: Vilma R
authors.initials: VR
authors.lastname: Martins
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism; D007797:Laminin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D017096:Prion Diseases / Q000235:genetics / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007797:Laminin; D018621:PrPC Proteins; C089141:laminin gamma 1; D019311:Staurosporine