title: A truncating mutation in Alzheimer's disease inactivates neuroligin-1 synaptic function.
abstract: Neuroligins (NLs) are cell-adhesion proteins that regulate synapse formation and function. Neuroligin 1 (NL1) promotes the formation of glutamatergic synapses and mediates long-term potentiation in mouse models. Thus, altered NL1 function could mediate the synaptic and memory deficits associated with Alzheimer's disease (AD). Here, we describe a frameshift mutation, c.875_876insTT, in the neuroligin 1 gene (NLGN1) in a patient with AD and familial history of AD. The insertion generates a premature stop codon in the extracellular domain of NL1 (p.Thr271fs). Expression of mutant NL1 shows accumulation of truncated NL1 proteins in the endoplasmic reticulum. In hippocampal neurons, the p.Thr271fs mutation abolishes the ability of NL1 to promote the formation of glutamatergic synapses. Our data support a role for inactivating mutations in NLGN1 in AD. Previous studies have reported rare mutations in X-linked NLGNL3 and NLGNL4 genes in patients with autism, which result in the inactivation of the mutant alleles. Therefore, together with a role in neurodevelopmental disorders, altered NL function could underlie the molecular mechanisms associated with brain diseases in the elderly.
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain.
authors.forename: Enriqueta
authors.initials: E
authors.lastname: Tristán-Clavijo
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
authors.forename: Rafael J
authors.initials: RJ
authors.lastname: Camacho-Garcia
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Robles-Lanuza
authors.affiliation: Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Agustín
authors.initials: A
authors.lastname: Ruiz
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: van der Zee
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.affiliation: Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Hernandez
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain. Electronic address: amm-ibis@us.es.
authors.forename: Amalia
authors.initials: A
authors.lastname: Martinez-Mir
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain. Electronic address: fgs@us.es.
authors.forename: Francisco G
authors.initials: FG
authors.lastname: Scholl
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000523:psychology; D000818:Animals; D019556:COS Cells; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism / Q000502:physiology*; D002522:Chlorocebus aethiops; D018388:Codon, Terminator / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D016368:Frameshift Mutation; D020868:Gene Silencing / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D017774:Long-Term Potentiation / Q000235:genetics; D008568:Memory; D051381:Rats; D013569:Synapses / Q000235:genetics* / Q000502:physiology*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D018388:Codon, Terminator; C093438:neuroligin 1
keywords: Alzheimer's disease; Mutation; NLGN1; Neuroligin; Synapse