Aperçu: G.M.
La
synthèse des protéines synaptiques est essentielle pour la modification
du cerveau par l'expérience et est aberrante dans plusieurs désordres
génétiquement définis, notamment le syndrome de l'X fragile (FX), une cause héréditaire
de l'autisme et de la déficience intellectuelle.
La
β-arrestine2 favorise la synthèse de protéines stimulées par mGlu5 dans
l'hippocampe et montre que la réduction génétique de β-arrestine2
corrige la plasticité et la cognition synaptique aberrante dans le
modèle de souris Fmr1- / y de FX.
En plus d'identifier une condition clé pour la synthèse de protéines
stimulées par mGlu5, ces données suggèrent que les modulateurs négatifs
polarisés par ß-arrestine2 de mGlu5 offrent des avantages significatifs
par rapport aux inhibiteurs de première génération pour le traitement de
FX et des troubles apparentés.
Cell Rep. 2017 Mar 21;18(12):2807-2814. doi: 10.1016/j.celrep.2017.02.075.
β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X
Stoppel LJ1, Auerbach BD2, Senter RK1, Preza AR1, Lefkowitz RJ3, Bear MF4.
Author information
- 1
- The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
- 2
- The Center for Hearing and Deafness, Department of Communicative Disorders and Sciences, The State University of New York at Buffalo, Buffalo, NY 14214, USA.
- 3
- Departments of Medicine and Biochemistry, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
- 4
- The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: mbear@mit.edu
Abstract
Synaptic
protein synthesis is essential for modification of the brain by
experience and is aberrant in several genetically defined disorders,
notably fragile X (FX), a heritable cause of autism
and intellectual disability. Neural activity directs local protein
synthesis via activation of metabotropic glutamate receptor 5 (mGlu5), yet how mGlu5
couples to the intracellular signaling pathways that regulate mRNA
translation is poorly understood. Here, we provide evidence that
β-arrestin2 mediates mGlu5-stimulated protein synthesis in
the hippocampus and show that genetic reduction of β-arrestin2 corrects
aberrant synaptic plasticity and cognition in the Fmr1-/y mouse model of FX. Importantly, reducing β-arrestin2 does not induce psychotomimetic activity associated with full mGlu5 inhibitors and does not affect Gq signaling. Thus, in addition to identifying a key requirement for mGlu5-stimulated protein synthesis, these data suggest that β-arrestin2-biased negative modulators of mGlu5 offer significant advantages over first-generation inhibitors for the treatment of FX and related disorders.
Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
- PMID: 28329674
- DOI: 10.1016/j.celrep.2017.02.075
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