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Monoallelic de novo AJAP1 loss-of-function variants disrupt trans-synaptic control of neurotransmitter release.
Früh, Simon; Boudkkazi, Sami; Koppensteiner, Peter; Sereikaite, Vita; Chen, Li-Yuan; Fernandez-Fernandez, Diego; Rem, Pascal D; Ulrich, Daniel; Schwenk, Jochen; Chen, Ziyang; Le Monnier, Elodie; Fritzius, Thorsten; Innocenti, Sabrina M; Besseyrias, Valérie; Trovò, Luca; Stawarski, Michal; Argilli, Emanuela; Sherr, Elliott H; van Bon, Bregje; Kamsteeg, Erik-Jan; Iascone, Maria; Pilotta, Alba; Cutrì, Maria R; Azamian, Mahshid S; Hernández-García, Andrés; Lalani, Seema R; Rosenfeld, Jill A; Zhao, Xiaonan; Vogel, Tiphanie P; Ona, Herda; Scott, Daryl A; Scheiffele, Peter; Strømgaard, Kristian; Tafti, Mehdi; Gassmann, Martin; Fakler, Bernd; Shigemoto, Ryuichi; Bettler, Bernhard.
Afiliación
  • Früh S; Department of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
  • Boudkkazi S; Institute of Physiology II, University of Freiburg, Hermann-Herderstrasse 7, 79104 Freiburg, Germany.
  • Koppensteiner P; Institute of Science and Technology Austria (IST Austria), Klosterneuburg, Austria.
  • Sereikaite V; Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
  • Chen LY; Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 7, 1005 Lausanne, Switzerland.
  • Fernandez-Fernandez D; Department of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
  • Rem PD; Department of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
  • Ulrich D; Department of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
  • Schwenk J; Institute of Physiology II, University of Freiburg, Hermann-Herderstrasse 7, 79104 Freiburg, Germany.
  • Chen Z; Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
  • Le Monnier E; Institute of Science and Technology Austria (IST Austria), Klosterneuburg, Austria.
  • Fritzius T; Department of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
  • Innocenti SM; Biocenter, University of Basel, Spitalstrasse 41, 4056 Basel, Switzerland.
  • Besseyrias V; Department of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
  • Trovò L; Department of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
  • Stawarski M; Department of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
  • Argilli E; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Sherr EH; Institute of Human Genetics and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • van Bon B; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Kamsteeg EJ; Institute of Human Genetics and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Iascone M; Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525, Netherlands.
  • Pilotta A; Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525, Netherlands.
  • Cutrì MR; Laboratorio Genetica Medica, ASST Papa Giovanni XXIII, Bergamo, Italy.
  • Azamian MS; UO Pediatria, Spedali Civili, Brescia, Italy.
  • Hernández-García A; UO Pediatria, Spedali Civili, Brescia, Italy.
  • Lalani SR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Zhao X; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Vogel TP; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Ona H; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Scott DA; Baylor Genetics, Houston, TX 77021, USA.
  • Scheiffele P; Division of Rheumatology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Strømgaard K; Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030, USA.
  • Tafti M; Division of Rheumatology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Gassmann M; Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030, USA.
  • Fakler B; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Shigemoto R; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Bettler B; Biocenter, University of Basel, Spitalstrasse 41, 4056 Basel, Switzerland.
Sci Adv ; 10(28): eadk5462, 2024 Jul 12.
Article en En | MEDLINE | ID: mdl-38985877
ABSTRACT
Adherens junction-associated protein 1 (AJAP1) has been implicated in brain diseases; however, a pathogenic mechanism has not been identified. AJAP1 is widely expressed in neurons and binds to γ-aminobutyric acid type B receptors (GBRs), which inhibit neurotransmitter release at most synapses in the brain. Here, we show that AJAP1 is selectively expressed in dendrites and trans-synaptically recruits GBRs to presynaptic sites of neurons expressing AJAP1. We have identified several monoallelic AJAP1 variants in individuals with epilepsy and/or neurodevelopmental disorders. Specifically, we show that the variant p.(W183C) lacks binding to GBRs, resulting in the inability to recruit them. Ultrastructural analysis revealed significantly decreased presynaptic GBR levels in Ajap1-/- and Ajap1W183C/+ mice. Consequently, these mice exhibited reduced GBR-mediated presynaptic inhibition at excitatory and inhibitory synapses, along with impaired synaptic plasticity. Our study reveals that AJAP1 enables the postsynaptic neuron to regulate the level of presynaptic GBR-mediated inhibition, supporting the clinical relevance of loss-of-function AJAP1 variants.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Sinapsis / Transmisión Sináptica / Neurotransmisores Límite: Animals / Female / Humans / Male Idioma: En Revista: Sci Adv Año: 2024 Tipo del documento: Article País de afiliación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Sinapsis / Transmisión Sináptica / Neurotransmisores Límite: Animals / Female / Humans / Male Idioma: En Revista: Sci Adv Año: 2024 Tipo del documento: Article País de afiliación: Suiza