| First Author | Beraldo FH | Year | 2016 |
| Journal | J Biol Chem | Volume | 291 |
| Issue | 42 | Pages | 21945-21955 |
| PubMed ID | 27563063 | Mgi Jnum | J:237291 |
| Mgi Id | MGI:5811949 | Doi | 10.1074/jbc.M116.738286 |
| Citation | Beraldo FH, et al. (2016) Regulation of Amyloid beta Oligomer Binding to Neurons and Neurotoxicity by the Prion Protein-mGluR5 Complex. J Biol Chem 291(42):21945-21955 |
| abstractText | 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 also for beta-amyloid oligomers (AbetaOs) 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 AbetaO-PrPC-mGluR5, as well as their interplay. Herein, we demonstrated that an existing complex containing PrPC-mGluR5 has an important role in AbetaO binding and activity in neurons. A peptide mimicking the binding site of laminin onto PrPC (Ln-gamma1) binds to PrPC and induces intracellular Ca2+ increase in neurons via the complex PrPC-mGluR5. Ln-gamma1 promotes internalization of PrPC and mGluR5 and transiently decreases AbetaO biding to neurons; however, the peptide does not impact AbetaO toxicity. Given that mGluR5 is critical for toxic signaling by AbetaOs 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. |
