title: Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer's disease.
abstract: Alzheimer's disease-related phenotypes in mice can be rescued by blockade of either cellular prion protein or metabotropic glutamate receptor 5. We sought genetic and biochemical evidence that these proteins function cooperatively as an obligate complex in the brain. We show that cellular prion protein associates via transmembrane metabotropic glutamate receptor 5 with the intracellular protein mediators Homer1b/c, calcium/calmodulin-dependent protein kinase II, and the Alzheimer's disease risk gene product protein tyrosine kinase 2 beta. Coupling of cellular prion protein to these intracellular proteins is modified by soluble amyloid-β oligomers, by mouse brain Alzheimer's disease transgenes or by human Alzheimer's disease pathology. Amyloid-β oligomer-triggered phosphorylation of intracellular protein mediators and impairment of synaptic plasticity in vitro requires Prnp-Grm5 genetic interaction, being absent in transheterozygous loss-of-function, but present in either single heterozygote. Importantly, genetic coupling between Prnp and Grm5 is also responsible for signalling, for survival and for synapse loss in Alzheimer's disease transgenic model mice. Thus, the interaction between metabotropic glutamate receptor 5 and cellular prion protein has a central role in Alzheimer's disease pathogenesis, and the complex is a potential target for disease-modifying intervention.
authors.affiliation: 1 Cellular Neuroscience, Neurodegeneration and Repair Program, Department of Neurology, Yale University School of Medicine, New Haven, CT 06536, USA 2 Graduate School of Cellular and Molecular Neuroscience, University of Tuebingen, D-72074 Tuebingen, Germany.
authors.forename: Laura T
authors.initials: LT
authors.lastname: Haas
authors.affiliation: 1 Cellular Neuroscience, Neurodegeneration and Repair Program, Department of Neurology, Yale University School of Medicine, New Haven, CT 06536, USA.
authors.forename: Santiago V
authors.initials: SV
authors.lastname: Salazar
authors.affiliation: 1 Cellular Neuroscience, Neurodegeneration and Repair Program, Department of Neurology, Yale University School of Medicine, New Haven, CT 06536, USA.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Kostylev
authors.affiliation: 1 Cellular Neuroscience, Neurodegeneration and Repair Program, Department of Neurology, Yale University School of Medicine, New Haven, CT 06536, USA.
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Um
authors.affiliation: 1 Cellular Neuroscience, Neurodegeneration and Repair Program, Department of Neurology, Yale University School of Medicine, New Haven, CT 06536, USA.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Kaufman
authors.affiliation: 1 Cellular Neuroscience, Neurodegeneration and Repair Program, Department of Neurology, Yale University School of Medicine, New Haven, CT 06536, USA stephen.strittmatter@yale.edu.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Strittmatter
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D064529:Receptor, Metabotropic Glutamate 5 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse; D064529:Receptor, Metabotropic Glutamate 5
keywords: Alzheimer’s disease; amyloid-beta oligomers; cellular prion protein; homer; metabotropic glutamate receptor 5