Therapeutic molecules and endogenous ligands regulate the interaction between brain cellular prion protein (PrPC) and metabotropic glutamate receptor 5 (mGluR5) [Molecular Bases of Disease]
August 22nd, 2014 by Haas, L. T., Kostylev, M. A., Strittmatter, S. M.
Soluble Amyloid-β oligomers (Aβo) can trigger Alzheimers disease (AD) pathophysiology by binding to cell surface Cellular Prion Protein (PrPC). PrPC interacts physically with metabotropic glutamate receptor 5 (mGluR5), and this interaction controls the transmission of neurotoxic signals to intracellular substrates. Since the interruption of the signal transduction from PrPC to mGluR5 has therapeutic potential for AD, we developed assays to explore the effect of endogenous ligands, agonists/antagonists and antibodies on the interaction between PrPC and mGluR5 in cell lines and mouse brain. We show that the PrPC segment of aa 91-153 mediates interaction with mGluR5. Agonists of mGluR5 increase the mGluR5/PrPC interaction, while mGluR5 antagonists suppress protein association. Synthetic Aβo promotes the protein interaction in mouse brain and transfected human embryonic kidney-293 (HEK-293) cell membrane preparations. Critically, the interaction of PrPC and mGluR5 is dramatically enhanced in the brains of familial AD transgenic model mice. In brain homogenates with Aβo, the interaction of PrPC and mGluR5 is reversed by mGluR5-directed antagonists or antibodies directed against PrPC segment of aa 91-153. Silent allosteric modulators of mGluR5 do not alter Glu or basal mGluR5 activity, but they disrupt Aβo-induced interaction of mGluR5 with PrPC. The assays described here have the potential to identify and develop new compounds that inhibit the interaction of PrPC and mGluR5, which plays a pivotal role in the pathogenesis of Alzheimer's disease by transmitting the signal from extracellular Aβo into the cytosol.