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Processing of the synaptic cell-adhesion molecule neurexin-3{beta} by Alzheimer's disease {alpha}- and {gamma}-secretases


Bot, N; Schweizer, C; Ben Halima, S; Fraering, P C (2011). Processing of the synaptic cell-adhesion molecule neurexin-3{beta} by Alzheimer's disease {alpha}- and {gamma}-secretases. Journal of Biological Chemistry, 286(4):2762-2773.

Abstract

Neurexins (NRXNs) are synaptic cell adhesion molecules having essential roles in the assembly and maturation of synapses into fully functional units. Immunocytochemical and electrophysiological studies have shown that specific binding, across the synaptic cleft, of the ectodomains of presynaptic NRXNs and postsynaptic Neuroligins (NLGNs) have the potential to bidirectionally coordinate and trigger synapse formation. Moreover, in vivo studies as well as genome-wide association studies pointed out implication of NRXNs in the pathogenesis of cognitive disorders including autism spectrum disorders (ASDs) and different types of addictions including opioid and alcohol dependences, suggesting an important role in synaptic function. Despite extensive investigations, the mechanisms by which NRXNs modulate the properties of synapses remain largely unknown. We report here that α- and γ-secretases can sequentially process neurexin-3β(NRXN3β), leading to the formation of two final products: a ~80 kDa N-terminal extracellular domain of Neurexin-3β (sNRXN3β) and ~12 kDa C-terminal intracellular NRXN3β domain (NRXN3β-ICD), with both of them being potentially implicated in the regulation of NRXNs and NLGNs functions at the synapses, or in yet unidentified signal transduction pathways. We further report that this processing is altered by several PS1 mutations in the catalytic subunit of the γ-secretase that causes early-onset familial Alzheimer's disease.

Abstract

Neurexins (NRXNs) are synaptic cell adhesion molecules having essential roles in the assembly and maturation of synapses into fully functional units. Immunocytochemical and electrophysiological studies have shown that specific binding, across the synaptic cleft, of the ectodomains of presynaptic NRXNs and postsynaptic Neuroligins (NLGNs) have the potential to bidirectionally coordinate and trigger synapse formation. Moreover, in vivo studies as well as genome-wide association studies pointed out implication of NRXNs in the pathogenesis of cognitive disorders including autism spectrum disorders (ASDs) and different types of addictions including opioid and alcohol dependences, suggesting an important role in synaptic function. Despite extensive investigations, the mechanisms by which NRXNs modulate the properties of synapses remain largely unknown. We report here that α- and γ-secretases can sequentially process neurexin-3β(NRXN3β), leading to the formation of two final products: a ~80 kDa N-terminal extracellular domain of Neurexin-3β (sNRXN3β) and ~12 kDa C-terminal intracellular NRXN3β domain (NRXN3β-ICD), with both of them being potentially implicated in the regulation of NRXNs and NLGNs functions at the synapses, or in yet unidentified signal transduction pathways. We further report that this processing is altered by several PS1 mutations in the catalytic subunit of the γ-secretase that causes early-onset familial Alzheimer's disease.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute for Regenerative Medicine (IREM)
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2011
Deposited On:17 Jan 2011 10:05
Last Modified:03 Aug 2017 15:24
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0021-9258
Additional Information:This research was originally published in Journal of Biological Chemistry. Bot N et al. Processing of the synaptic cell-adhesion molecule neurexin-3{beta} by Alzheimer's disease {alpha}- and {gamma}-secretases. 2010; 286 (4) 2762-2773 © the American Society for Biochemistry and Molecular Biology.
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1074/jbc.M110.142521
Official URL:http://www.jbc.org/content/early/2010/11/17/jbc.M110.142521.long
PubMed ID:21084300

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