Disease-associated Mutations in the Prion Protein Impair Laminin-induced Process Outgrowth and Survival

Author(s)

Machado, Cleiton F. ^{[1, 2]} ; Beraldo, Flavio H. ^{[3, 4]} ; Santos, Tiago G. ^{[1, 2]} ; Bourgeon, Dominique ^{[1, 2]} ; Landemberger, Michele C. ^{[1, 2]} ; Roffe, Martin ^{[1, 2]} ; Martins, Vilma R. ^{[1, 2]}

Affiliation

^[1] AC Camargo Hosp, Int Res Ctr, BR-01508010 Sao Paulo - Brazil

^[2] CNPq MCT FAPESP, Natl Inst Translat Neurosci, BR-01508010 Sao Paulo - Brazil

^[3] Univ Western Ontario, Dept Physiol & Pharmacol, London, ON N6A 5K8 - Canada

^[4] Univ Western Ontario, Robarts Res Inst, J Allyn Taylor Ctr Cell Biol, Mol Brain Res Grp, London, ON N6A 5K8 - Canada

• Document type: Journal article
• Source: Journal of Biological Chemistry; v. 287, n. 52, p. 43777-43788, DEC 21 2012.
• Web of Science Citations: 4

Abstract

Prions, the agents of transmissible spongiform encephalopathies, require the expression of prion protein (PrPC) to propagate disease. PrPC is converted into an abnormal insoluble form, PrPSc, that gains neurotoxic activity. Conversely, clinical manifestations of prion disease may occur either before or in the absence of PrPSc deposits, but the loss of normal PrPC function contribution for the etiology of these diseases is still debatable. Prion disease-associated mutations in PrPC represent one of the best models to understand the impact of PrPC loss-of-function. PrPC associates with various molecules and, in particular, the interaction of PrPC with laminin (Ln) modulates neuronal plasticity and memory formation. To assess the functional alterations associated with PrPC mutations, wild-type and mutated PrPC proteins were expressed in a neural cell line derived from a PrPC-null mouse. Treatment with the laminin gamma 1 chain peptide (Ln gamma 1), which mimics the Ln binding site for PrPC, increased intracellular calcium in cells expressing wild-type PrPC, whereas a significantly lower response was observed in cells expressing mutated PrPC molecules. The Ln gamma 1 did not promote process outgrowth or protect against staurosporine-induced cell death in cells expressing mutated PrPC molecules in contrast to cells expressing wild-type PrPC. The co-expression of wild-type PrPC with mutated PrPC molecules was able to rescue the Ln protective effects, indicating the lack of negative dominance of PrPC mutated molecules. These results indicate that PrPC mutations impair process outgrowth and survival mediated by Ln gamma 1 peptide in neural cells, which may contribute to the pathogenesis of genetic prion diseases. (AU)

• FAPESP's process: 08/04776-5 - Mutant prion proteins expression in astrocytes: Roles and Impact.
• Grantee: Dominique Michel Gwen Bourgeon
• Support Opportunities: Scholarships in Brazil - Post-Doctoral