title: 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.
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS UMR8104, 24 rue du Faubourg Saint Jacques 75014, Paris, France. malik.khelfaoui@inserm.fr
authors.forename: Malik
authors.initials: M
authors.lastname: Khelfaoui
authors.forename: Alice
authors.initials: A
authors.lastname: Pavlowsky
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Powell
authors.forename: Pamela
authors.initials: P
authors.lastname: Valnegri
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Cheong
authors.forename: Yann
authors.initials: Y
authors.lastname: Blandin
authors.forename: Maria
authors.initials: M
authors.lastname: Passafaro
authors.forename: John G R
authors.initials: JG
authors.lastname: Jefferys
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Pierre
authors.initials: P
authors.lastname: Billuart
mesh_terms: D000818:Animals; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D004705:Endocytosis; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein
chemical_list: D003598:Cytoskeletal Proteins; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C498439:Ophn1 protein, mouse; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein