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Neurobiol Aging. 2015 Dec;36(12):3171-3175. doi: 10.1016/j.neurobiolaging.2015.09.004. Epub 2015 Sep 10.

A truncating mutation in Alzheimer's disease inactivates neuroligin-1 synaptic function.

Author information

1
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.
2
Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
3
Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
4
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
5
Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain. Electronic address: amm-ibis@us.es.
6
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.

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.

KEYWORDS:

Alzheimer's disease; Mutation; NLGN1; Neuroligin; Synapse

[Indexed for MEDLINE]

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