title: The Rho-linked mental retardation protein OPHN1 controls synaptic vesicle endocytosis via endophilin A1.
abstract: Neurons transmit information at chemical synapses by releasing neurotransmitters that are stored in synaptic vesicles (SVs) at the presynaptic site. After release, these vesicles need to be efficiently retrieved in order to maintain synaptic transmission. In concurrence, malfunctions in SV recycling have been associated with cognitive disorders. Oligophrenin-1 (OPHN1) encodes a Rho-GTPase-activating protein (Rho-GAP) whose loss of function causes X-linked mental retardation. OPHN1 is highly expressed in the brain and present both pre- and postsynaptically in neurons. Previous studies report that postsynaptic OPHN1 is important for dendritic spine morphogenesis, but its function at the presynaptic site remains largely unexplored. Here, we present evidence that reduced or defective OPHN1 signaling impairs SV cycling at hippocampal synapses. In particular, we show that OPHN1 knockdown affects the kinetic efficiency of endocytosis. We further demonstrate that OPHN1 forms a complex with endophilin A1, a protein implicated in membrane curvature generation during SV endocytosis and, importantly, that OPHN1's interaction with endophilin A1 and its Rho-GAP activity are important for its function in SV endocytosis. Our findings suggest that defects in efficient SV retrieval may contribute to the pathogenesis of OPHN1-linked cognitive impairment.
authors.affiliation: Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York, NY 11724, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Nakano-Kobayashi
authors.forename: Nael Nadif
authors.initials: NN
authors.lastname: Kasri
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Newey
authors.forename: Linda
authors.initials: L
authors.lastname: Van Aelst
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology*; D005456:Fluorescent Dyes / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D013572:Synaptic Vesicles / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D005456:Fluorescent Dyes; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C498439:Ophn1 protein, mouse; D011993:Recombinant Fusion Proteins; C504641:endophilin A1 protein, mouse