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Inhibition of RhoA pathway rescues the endocytosis defects in Oligophrenin1 mouse model of mental retardation.

Abstract : The patho-physiological hypothesis of mental retardation caused by the deficiency of the RhoGAP Oligophrenin1 (OPHN1), relies on the well-known functions of Rho GTPases on neuronal morphology, i.e. dendritic spine structure. Here, we describe a new function of this Bin/Amphiphysin/Rvs domain containing protein in the control of clathrin-mediated endocytosis (CME). Through interactions with Src homology 3 domain containing proteins involved in CME, OPHN1 is concentrated to endocytic sites where it down-regulates the RhoA/ROCK signaling pathway and represses the inhibitory function of ROCK on endocytosis. Indeed disruption of Ophn1 in mice reduces the endocytosis of synaptic vesicles and the post-synaptic alpha-amino-3-hydroxy-5-methylisoazol-4-propionate (AMPA) receptor internalization, resulting in almost a complete loss of long-term depression in the hippocampus. Finally, pharmacological inhibition of this pathway by ROCK inhibitors fully rescued not only the CME deficit in OPHN1 null cells but also synaptic plasticity in the hippocampus from Ophn1 null model. Altogether, we uncovered a new patho-physiological mechanism for intellectual disabilities associated to mutations in RhoGTPases linked genes and also opened new directions for therapeutic approaches of congenital mental retardation.
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https://www.hal.inserm.fr/inserm-00424014
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Submitted on : Tuesday, October 13, 2009 - 4:52:00 PM
Last modification on : Thursday, April 9, 2020 - 11:54:36 AM
Long-term archiving on: : Wednesday, June 16, 2010 - 12:43:12 AM

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Malik Khelfaoui, Alice Pavlowsky, Andrew Powell, Pamela Valnegri, Kenneth Cheong, et al.. Inhibition of RhoA pathway rescues the endocytosis defects in Oligophrenin1 mouse model of mental retardation.. Human Molecular Genetics, Oxford University Press (OUP), 2009, 18 (14), pp.2575-83. ⟨10.1093/hmg/ddp189⟩. ⟨inserm-00424014⟩

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