title: Regulation of Amyloid β Oligomer Binding to Neurons and Neurotoxicity by the Prion Protein-mGluR5 Complex.
abstract: The prion protein (PrPC) has been suggested to operate as a scaffold/receptor protein in neurons, participating in both physiological and pathological associated events. PrPC, laminin, and metabotropic glutamate receptor 5 (mGluR5) form a protein complex on the plasma membrane that can trigger signaling pathways involved in neuronal differentiation. PrPCand mGluR5 are co-receptors also for β-amyloid oligomers (AβOs) and have been shown to modulate toxicity and neuronal death in Alzheimer's disease. In the present work, we addressed the potential crosstalk between these two signaling pathways, laminin-PrPC-mGluR5 or AβO-PrPC-mGluR5, as well as their interplay. Herein, we demonstrated that an existing complex containing PrPC-mGluR5 has an important role in AβO binding and activity in neurons. A peptide mimicking the binding site of laminin onto PrPC(Ln-γ1) binds to PrPCand induces intracellular Ca2+increase in neurons via the complex PrPC-mGluR5. Ln-γ1 promotes internalization of PrPCand mGluR5 and transiently decreases AβO biding to neurons; however, the peptide does not impact AβO toxicity. Given that mGluR5 is critical for toxic signaling by AβOs and in prion diseases, we tested whether mGlur5 knock-out mice would be susceptible to prion infection. Our results show mild, but significant, effects on disease progression, without affecting survival of mice after infection. These results suggest that PrPC-mGluR5 form a functional response unit by which multiple ligands can trigger signaling. We propose that trafficking of PrPC-mGluR5 may modulate signaling intensity by different PrPCligands.
authors: From the Robarts Research Institute and.
authors: Flavio H
authors: http://orcid.org/0000-0001-7638-2007
authors: FH
authors: Beraldo
authors: From the Robarts Research Institute and.
authors: Valeriy G
authors: VG
authors: Ostapchenko
authors: From the Robarts Research Institute and the Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5B7,Canada.
authors: Fabiana A
authors: FA
authors: Caetano
authors: From the Robarts Research Institute and the Universidade Estadual de Montes Claros, Montes Claros, MG 39401-089, Brazil.
authors: Andre L S
authors: AL
authors: Guimaraes
authors: From the Robarts Research Institute and the Programa de Biologia Estrutural, Instituto de Bioquimica Medica Leopoldo de Meis, Instututo Nacional de Biologia Estrutural e Bioimagem, Centro Nacional de Ressonacia Magnetica Nuclear Jiri Jonas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, Brazil.
authors: Giulia D S
authors: GD
authors: Ferretti
authors: the Center for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta T6G 2M8, Canada.
authors: Nathalie
authors: N
authors: Daude
authors: the Center for Brain Health, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors: Lisa
authors: L
authors: Bertram
authors: From the Robarts Research Institute and the Instituto de Ciências Exatas e Biológicas, Departamento de Ciências Biológicas, Universidade Federal de Ouro Preto, Campus Morro do Cruzeiro S/N, Ouro Preto, Minas Gerais 35400-000, Brazil.
authors: Katiane O P C
authors: KO
authors: Nogueira
authors: the Programa de Biologia Estrutural, Instituto de Bioquimica Medica Leopoldo de Meis, Instututo Nacional de Biologia Estrutural e Bioimagem, Centro Nacional de Ressonacia Magnetica Nuclear Jiri Jonas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, Brazil.
authors: Jerson L
authors: JL
authors: Silva
authors: the Center for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta T6G 2M8, Canada.
authors: David
authors: D
authors: Westaway
authors: the Center for Brain Health, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors: Neil R
authors: NR
authors: Cashman
authors: the International Center for Research and Education, A. C. Camargo Cancer Center, São Paulo, SP CEP 01509-010, Brazil, and.
authors: Vilma R
authors: VR
authors: Martins
authors: From the Robarts Research Institute and the Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5B7,Canada, the Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A 3K7, Canada.
authors: Vania F
authors: VF
authors: Prado
authors: From the Robarts Research Institute and the Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5B7,Canada, the Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A 3K7, Canada mprado@robarts.ca.
authors: Marco A M
authors: MA
authors: Prado
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D017096:Prion Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055503:Protein Multimerization; D021381:Protein Transport / Q000235:genetics; D064529:Receptor, Metabotropic Glutamate 5 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; C578936:Grm5 protein, mouse; D010446:Peptide Fragments; D018621:PrPC Proteins; D064529:Receptor, Metabotropic Glutamate 5; C075222:amyloid beta-protein (1-42); D002118:Calcium
keywords: Alzheimer disease; Protein trafficking; calcium; laminin; metabotropic glutamate receptor (mGluR); metabotropic glutamate receptor 5; prion