Beraldo F.H.,University of Western Ontario |
Ostapchenko V.G.,University of Western Ontario |
Caetano F.A.,University of Western Ontario |
Guimaraes A.L.S.,University of Western Ontario |
And 13 more authors.
Journal of Biological Chemistry | Year: 2016
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. PrPC and mGluR5 are co-receptors alsoforβ-amyloidoligomers(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-PrPCmGluR5, as well as their interplay. Herein, we demonstrated that an existing complex containing PrPC-mGluR5 has an important role in AβObinding and activity in neurons. A peptide mimicking the binding site of laminin onto PrPC (Ln-γ1) binds to PrPC and induces intracellular Ca2+ increase in neurons via the complex PrPC-mGluR5. Ln-γ1 promotes internalization of PrPC and mGluR5 and transiently decreases AβO biding to neurons; however, the peptide does not impact Aβ Otoxicity. 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 PrPC ligands. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.