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Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer's disease.

Authors
 Laura T. Haas  ;  Santiago V. Salazar  ;  Mikhail A. Kostylev  ;  Ji Won Um  ;  Adam C. Kaufman  ;  Stephen M. Strittmatter 
Citation
 BRAIN, Vol.139(Pt2) : 526-546, 2016 
Journal Title
 BRAIN 
ISSN
 0006-8950 
Issue Date
2016
MeSH
Alzheimer Disease/genetics ; Alzheimer Disease/metabolism* ; Alzheimer Disease/pathology ; Animals ; Frontal Lobe/metabolism ; Frontal Lobe/pathology ; HEK293 Cells ; Humans ; Intracellular Fluid/metabolism* ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Organ Culture Techniques ; Prion Proteins ; Prions/genetics ; Prions/metabolism* ; Protein Binding/physiology ; Receptor, Metabotropic Glutamate 5/genetics ; Receptor, Metabotropic Glutamate 5/metabolism* ; Signal Transduction/physiology*
Keywords
Alzheimer’s disease ; amyloid-beta oligomers ; cellular prion protein ; homer ; metabotropic glutamate receptor 5
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.
Full Text
http://brain.oxfordjournals.org/content/139/2/526
DOI
10.1093/brain/awv356
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실) > 1. Journal Papers
Yonsei Authors
Um, Ji Won(엄지원)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/146390
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