Regulation of Amyloid β Oligomer Binding to Neurons and Neurotoxicity by the Prion Protein-mGluR5 Complex.

Autor:	Beraldo FH; From the Robarts Research Institute and., Ostapchenko VG; From the Robarts Research Institute and., Caetano FA; From the Robarts Research Institute and the Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5B7,Canada., Guimaraes AL; From the Robarts Research Institute and the Universidade Estadual de Montes Claros, Montes Claros, MG 39401-089, Brazil., Ferretti GD; 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., Daude N; the Center for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta T6G 2M8, Canada., Bertram L; the Center for Brain Health, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada., Nogueira KO; 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., Silva JL; 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., Westaway D; the Center for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta T6G 2M8, Canada., Cashman NR; the Center for Brain Health, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada., Martins VR; the International Center for Research and Education, A. C. Camargo Cancer Center, São Paulo, SP CEP 01509-010, Brazil, and., Prado VF; 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., Prado MA; 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.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2016 Oct 14; Vol. 291 (42), pp. 21945-21955. Date of Electronic Publication: 2016 Aug 25.
DOI:	10.1074/jbc.M116.738286
Abstrakt:	The prion protein (PrP C ) has been suggested to operate as a scaffold/receptor protein in neurons, participating in both physiological and pathological associated events. PrP C , laminin, and metabotropic glutamate receptor 5 (mGluR5) form a protein complex on the plasma membrane that can trigger signaling pathways involved in neuronal differentiation. PrP C and 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-PrP C -mGluR5 or AβO-PrP C -mGluR5, as well as their interplay. Herein, we demonstrated that an existing complex containing PrP C -mGluR5 has an important role in AβO binding and activity in neurons. A peptide mimicking the binding site of laminin onto PrP C (Ln-γ1) binds to PrP C and induces intracellular Ca 2+ increase in neurons via the complex PrP C -mGluR5. Ln-γ1 promotes internalization of PrP C and 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 PrP C -mGluR5 form a functional response unit by which multiple ligands can trigger signaling. We propose that trafficking of PrP C -mGluR5 may modulate signaling intensity by different PrP C ligands. (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)
Databáze:	MEDLINE
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