title: Therapeutic molecules and endogenous ligands regulate the interaction between brain cellular prion protein (PrPC) and metabotropic glutamate receptor 5 (mGluR5).
abstract: Soluble Amyloid-β oligomers (Aβo) can trigger Alzheimer disease (AD) pathophysiology by binding to cell surface cellular prion protein (PrP(C)). PrP(C) interacts physically with metabotropic glutamate receptor 5 (mGluR5), and this interaction controls the transmission of neurotoxic signals to intracellular substrates. Because the interruption of the signal transduction from PrP(C) 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 PrP(C) and mGluR5 in cell lines and mouse brain. We show that the PrP(C) segment of amino acids 91-153 mediates the interaction with mGluR5. Agonists of mGluR5 increase the mGluR5-PrP(C) interaction, whereas mGluR5 antagonists suppress protein association. Synthetic Aβo promotes the protein interaction in mouse brain and transfected HEK-293 cell membrane preparations. The interaction of PrP(C) and mGluR5 is enhanced dramatically in the brains of familial AD transgenic model mice. In brain homogenates with Aβo, the interaction of PrP(C) and mGluR5 is reversed by mGluR5-directed antagonists or antibodies directed against the PrP(C) segment of amino acids 91-153. Silent allosteric modulators of mGluR5 do not alter Glu or basal mGluR5 activity, but they disrupt the Aβo-induced interaction of mGluR5 with PrP(C). The assays described here have the potential to identify and develop new compounds that inhibit the interaction of PrP(C) and mGluR5, which plays a pivotal role in the pathogenesis of Alzheimer disease by transmitting the signal from extracellular Aβo into the cytosol.
authors.affiliation: From the Cellular Neuroscience, Neurodegeneration and Repair Program, Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06536 and the Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, D-72074 Tübingen, Germany.
authors.forename: Laura T
authors.initials: LT
authors.lastname: Haas
authors.affiliation: From the Cellular Neuroscience, Neurodegeneration and Repair Program, Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06536 and.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Kostylev
authors.affiliation: From the Cellular Neuroscience, Neurodegeneration and Repair Program, Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06536 and stephen.strittmatter@yale.edu.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Strittmatter
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D001665:Binding Sites; D001681:Biological Assay; D001923:Brain Chemistry; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D010449:Peptide Mapping; D018621:PrPC Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies; D008024:Ligands; D018621:PrPC Proteins; D064529:Receptor, Metabotropic Glutamate 5; D011994:Recombinant Proteins; D054852:Small Molecule Libraries
keywords: Alzheimer Disease; Amyloid-β (AB); Metabotropic Glutamate Receptor (mGluR); Neurodegenerative Disease; Prion; Protein-Protein Interaction; Therapeutic Modulation