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

Laboratory of Molecular and Cellular Biology of Alzheimer Disease, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), CH-1015 Lausanne, Switzerland.
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2010; 286(4):2762-73. DOI: 10.1074/jbc.M110.142521
Source: PubMed


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 α- and γ-secretases can sequentially process NRXN3β, leading to the
formation of two final products, an ∼80-kDa N-terminal extracellular domain of Neurexin-3β (sNRXN3β) and an ∼12-kDa C-terminal
intracellular NRXN3β domain (NRXN3β-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 γ-secretase that cause early-onset familial Alzheimer disease.

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    • "A large number of γ-secretase substrates have recently been identified and the number is now approaching approximately 90 [83–85]. Notably, many γ-secretase substrates are synaptic surface proteins [83–85], including N-cadherin [86], ErbB4 [87,88], nectin-1α [89], syndecan-1/2/3 [85,90], GluR3 (GluA3) [91], ephrinB1/2 [92–94], EphA4/B2 [95,96], LAR [97], neurexin-1/3β [98,99] and neuroligin-1 [30,31]. This suggests that γ-secretase could act on these proteins to regulate synapse structure and function. "
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    ABSTRACT: Long-term depression (LTD) reduces the functional strength of excitatory synapses through mechanisms that include the removal of AMPA glutamate receptors from the postsynaptic membrane. LTD induction is also known to result in structural changes at excitatory synapses, including the shrinkage of dendritic spines. Synaptic adhesion molecules are thought to contribute to the development, function and plasticity of neuronal synapses largely through their trans-synaptic adhesions. However, little is known about how synaptic adhesion molecules are altered during LTD. We report here that NGL-3 (netrin-G ligand-3), a postsynaptic adhesion molecule that trans-synaptically interacts with the LAR family of receptor tyrosine phosphatases and intracellularly with the postsynaptic scaffolding protein PSD-95, undergoes a proteolytic cleavage process. NGL-3 cleavage is induced by NMDA treatment in cultured neurons and low-frequency stimulation in brain slices and requires the activities of NMDA glutamate receptors, matrix metalloproteinases (MMPs) and presenilin/γ-secretase. These results suggest that NGL-3 is a novel substrate of MMPs and γ-secretase and that NGL-3 cleavage may regulate synaptic adhesion during LTD.
    Full-text · Article · Jan 2014 · Philosophical Transactions of The Royal Society B Biological Sciences
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    • "The effect of these mutations on NRXN3 processing has been elucidated by overexpressing them in Chinese hamster ovary cells stably expressing NRXN3. The mutated proteins increased NRXN3b-CTF levels and decreased NRXN3b-ICD formation (Bot et al., 2011). These data suggest that mutated forms of PS1/g-secretase impair NRXN3 processing and may cause the accumulation of the intracellular NRXN3 C-terminal fragment. "
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    ABSTRACT: Synaptic damage is a critical hallmark of Alzheimer's disease, and the best correlate with cognitive impairment ante mortem. Synapses, the loci of communication between neurons, are characterized by signature protein combinations arrayed at tightly apposed pre- and post-synaptic sites. The most widely studied trans-synaptic junctional complexes, which direct synaptogenesis and foster the maintenance and stability of the mature terminal, are conjunctions of presynaptic neurexins and postsynaptic neuroligins. Fluctuations in the levels of neuroligins and neurexins can sway the balance between excitatory and inhibitory neurotransmission in the brain, and could lead to damage of synapses and dendrites. This review summarizes current understanding of the roles of neurexins and neuroligins proteolytic processing in synaptic plasticity in the human brain, and outlines their possible roles in β-amyloid metabolism and function, which are central pathogenic events in Alzheimer's disease progression.
    Full-text · Article · Nov 2013 · Neurobiology of aging
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    • "Presenilins are key proteins in the release of neurotransmitters and regulation of long-term potentiation [69]. The binding partners neurexin and neuroligin are both substrates of the PSEN/γ-secretase and have been described as pivotal proteins in pre-synaptic and post-synaptic junctions [70] [71] [72]. These proteins have also been depicted as important regulatory components in the maintenance of vascular functions since they participate in the metabolism of endothelial and vascular smooth muscle cells [73]. "
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    ABSTRACT: Alzheimer's disease (AD) dementia impacts all facets of higher order cognitive function and is characterized by the presence of distinctive pathological lesions in the gray matter (GM). The profound alterations in GM structure and function have fostered the view that AD impacts are primarily a consequence of GM damage. However, the white matter (WM) represents about 50% of the cerebrum and this area of the brain is substantially atrophied and profoundly abnormal in both sporadic AD (SAD) and familial AD (FAD). We examined the WM biochemistry by ELISA and Western blot analyses of key proteins in 10 FAD cases harboring mutations in the presenilin genes PSEN1 and PSEN2 as well as in 4 non-demented control (NDC) individuals and 4 subjects with SAD. The molecules examined were direct substrates of PSEN1 such as Notch-1 and amyloid precursor protein (APP). In addition, apolipoproteins, axonal transport molecules, cytoskeletal and structural proteins, neurotrophic factors and synaptic proteins were examined. PSEN-FAD subjects had, on average, higher amounts of WM amyloid-beta (Aβ) peptides compared to SAD, which may play a role in the devastating dysfunction of the brain. However, the PSEN-FAD mutations we examined did not produce uniform increases in the relative proportions of Aβ42 and exhibited substantial variability in total Aβ levels. These observations suggest that neurodegeneration and dementia do not depend solely on enhanced Aβ42 levels. Our data revealed additional complexities in PSEN-FAD individuals. Some direct substrates of γ-secretase, such as Notch, N-cadherin, Erb-B4 and APP, deviated substantially from the NDC group baseline for some, but not all, mutation types. Proteins that were not direct γ-secretase substrates, but play key structural and functional roles in the WM, likewise exhibited varied concentrations in the distinct PSEN mutation backgrounds. Detailing the diverse biochemical pathology spectrum of PSEN mutations may offer valuable insights into dementia progression and the design of effective therapeutic interventions for both SAD and FAD.
    Full-text · Article · Oct 2013 · American Journal of Neurodegenerative Diseases
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