Processing of the Synaptic Cell Adhesion Molecule Neurexin-3β by Alzheimer Disease α- and γ-Secretases

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 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 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 ␣-and ␥-secretases can sequentially process NRXN3␤, leading to the formation of two final products, an ϳ80-kDa N-terminal extracellular domain of Neurexin-3␤ (sNRXN3␤) and an ϳ12-kDa C-terminal intracellular NRXN3␤ domain (NRXN3␤-ICD), both of them being potentially implicated in the regulation of NRXNs and neuroligins 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 ␥-secretase that cause early-onset familial Alzheimer disease.

Carbonic anhydrase-related protein CA10 is an evolutionarily conserved pan-neurexin ligand

“…6 and 7), suggesting that CA10 associates with neurexins in the secretory pathway and serves, at least in part, as a neurexin chaperone during surface transport. Alternatively, it is possible that CA10 attenuates the turnover of surface neurexins by blocking their proteolytic turnover by metalloprotease and γ-secretase (32,33).…”

Calsyntenins Function as Synaptogenic Adhesion Molecules in Concert with Neurexins

“…Intriguingly, CST-1 and CST-3 have been identified as potential biomarkers of AD (Ringman et al, 2012; Yin et al, 2009). Recently, several γ-secretase mutations impair Nrx-3β processing, linking Nrxs with AD pathogenesis (Bot et al, 2011). It is tempting to speculate that the misregulation of CST-3 and/or Nrx proteolytic processing might induce a subset of early-onset familial AD.…”

A Combined Transgenic Proteomic Analysis and Regulated Trafficking of Neuroligin-2

“…Although neurexins are expressed mainly as transmembrane proteins, secreted forms of neurexin 3 can be generated by alternative splicing (62). Furthermore, multiple subtypes of neurexins are subject to proteolytic processing by metalloproteases and presenilins resulting in ectodomain shedding (63,64). Thus the soluble neurexin 1␤ ectodomain used here to trigger endocytosis may mimic the shed ectodomain.…”