English   español  
Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/143269
Share/Impact:
Statistics
logo share SHARE   Add this article to your Mendeley library MendeleyBASE
Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL
Exportar a otros formatos:

Title

Identification of causative and susceptibility variants in the neurexin-neuroligin pathway in patients with Alzheimer's disease. The role of a truncating mutation in Neuroligin 1

AuthorsTristán Clavijo, E. ; Camacho García, R. J. ; Robles Lanuza, Estefanía ; Ruiz, Agustín; Hernández, Isabel; Martínez Mir, Amalia ; Scholl, Francisco G.
Issue DateSep-2015
Citation16th National Congress of the Spanish Society of Neuroscience (2015)
AbstractNeurexins (NRXN) and neuroligins (NLGN) are synaptic cell-adhesion proteins involved in neurodevelopmental disorders, as autism and intellectual disability. Previously, we have postulated a role of NRNX-NLGN in Alzheimer's disease (AD). Here, we present genetic and functional approaches to identify variants of the NRNX-NLGN pathway in AD patients. Using next-generation sequencing, we have studied a panel of 36 genes of the NRNX-NLGN synaptic pathway in 192 AD patients. Potential causal variants were studied by in silico analysis and validated by Sanger sequencing. Susceptibility variants were analyzed by manual inspection in IGV (Integrative Genomics Viewer). Functional studies of selected variants were performed in N2A and COS cells and cultured hipocampal neurons. To identify susceptibility alleles, we selected SNPs whose allelic frequency differed among the genotyped AD patients and the control databases. These SNPs were then genotyped in a geographically-matched control population. On the other hand, potential causative mutations were selected among novel variants with a predicted pathogenic effect. We present a two base-pair insertion in NLGN1 (p.Thr271fs) in a patient with familial history of AD. The frameshift mutation in NLGN1 predicts a premature STOP codon that truncates the extracellular domain. We generated expression vectors for the p.Thr271fs mutation. In western blot experiments we detected a band of ~130 kD corresponding to wild type NLGN1. In contrast, the p.Thr271fs mutation resulted in truncated proteins of ~30 kDa. Localization studies in COS cells showed that p.Thr271fs NLGN1 failed to reach the plasma membrane and accumulated in the ER. In neurons, NLGN1 induces the formation of glutamatergic synapses. We showed that p.Thr271fs NLGN1 failed to induce the formation of glutamatergic synapses and accumulated in the soma of transfected neurons. Thus, the synaptic activity of NLGN1 was abolished by the AD-associated p.Thr271fs mutation. Our data report the first inactivating mutation in the NLGN1 gene in AD patients and support a role for the NRXN-NLGN pathway in the etiology of AD.
DescriptionPóster presentado en el 16th National Congress of the Spanish Society of Neuroscience (SENC 2015), celebrado el Granada del 23 al 25 de septiembre de 2015.
URIhttp://hdl.handle.net/10261/143269
Appears in Collections:(IBIS) Comunicaciones congresos
Files in This Item:
File Description SizeFormat 
accesoRestringido.pdf15,38 kBAdobe PDFThumbnail
View/Open
Show full item record
Review this work
 


WARNING: Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.