Activity-Dependent Proteolytic Cleavage of Neuroligin-1

Department of Neuropathology and Neuroscience, The University of Tokyo, Hongo 7-3-1, Bunkyo, Tokyo 113-0033, Japan.
Neuron (Impact Factor: 15.05). 10/2012; 76(2):410-22. DOI: 10.1016/j.neuron.2012.10.003
Source: PubMed


Neuroligin (NLG), a postsynaptic adhesion molecule, is involved in the formation of synapses by binding to a cognate presynaptic ligand, neurexin. Here we report that neuroligin-1 (NLG1) undergoes ectodomain shedding at the juxtamembrane stalk region to generate a secreted form of NLG1 and a membrane-tethered C-terminal fragment (CTF) in adult rat brains in vivo as well as in neuronal cultures. Pharmacological and genetic studies identified ADAM10 as the major protease responsible for NLG1 shedding, the latter being augmented by synaptic NMDA receptor activation or interaction with soluble neurexin ligands. NLG1-CTF was subsequently cleaved by presenilin/γ-secretase. Secretion of soluble NLG1 was significantly upregulated under a prolonged epileptic seizure condition, and inhibition of NLG1 shedding led to an increase in numbers of dendritic spines in neuronal cultures. Collectively, neuronal activity-dependent proteolytic processing of NLG1 may negatively regulate the remodeling of spines at excitatory synapses.

1 Follower
38 Reads
  • Source
    • "Similarly, it has recently been shown that NLG-1 undergoes ectodomain shedding by ADAM10 (Suzuki et al., 2012). Interestingly , neuronal activity increased shedding of NLG-1 and thus might negatively regulate remodeling of spines (Suzuki et al., 2012). In line with this, also Calsyntenin 3 is subject to ectodomain shedding (Araki et al., 2004), whereas membrane anchored Calsyntenin 3 displays a higher synaptogenic activity than its secreted form (Pettem et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Amyloid precursor protein (APP) plays a central role in Alzheimer’s disease (AD) and has essential synapse promoting functions. Synaptogenic activity as well as cell adhesion properties of APP presumably depend on trans-cellular dimerization via its extracellular domain. Since neuronal APP is extensively processed by secretases, it raises the question if APP shedding affects its cell adhesion and synaptogenic properties. We show that inhibition of APP shedding using cleavage deficient forms of APP or a dominant negative α-secretase strongly enhanced its cell adhesion and synaptogenic activity suggesting that synapse promoting function of APP is tightly regulated by α-secretase mediated processing, similar to other trans-cellular synaptic adhesion molecules.
    Frontiers in Cellular Neuroscience 11/2014; 8(410). DOI:10.3389/fncel.2014.00410 · 4.29 Impact Factor
  • Source
    • "Our results are reminiscent of the recently reported activity-dependent cleavage of neuroligin-1 mediated by MMP-9/ADAM-10 and γ-secretase [30,31]. Neurexin-1β and neurexin-3β, which interact with neuroligins, have also been shown to be substrates of γ-secretase [98,99]. "
    [Show abstract] [Hide abstract]
    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.
    Philosophical Transactions of The Royal Society B Biological Sciences 01/2014; 369(1633):20130158. DOI:10.1098/rstb.2013.0158 · 7.06 Impact Factor
  • Source
    • "(B) Activity-dependent redistribution of adhesion molecules over the axonal membrane can facilitate synapse formation (Fu and Huang, 2010). (C) Activity-dependent cleavage of synaptic adhesion molecules could induce synapse disassembly or plasticity (Matsumoto-Miyai et al., 2009; O'Connor et al., 2009; Peixoto et al., 2012; Suzuki et al., 2012). (D) Activity-dependent changes in binding properties of adhesion molecules (Kim et al., 2011a,b) could affect synaptic properties. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Synaptic connections in our brains change continuously and throughout our lifetime. Despite ongoing synaptic changes, a healthy balance between excitation and inhibition is maintained by various forms of homeostatic and activity-dependent adaptations, ensuring stable functioning of neuronal networks. In this review we summarize experimental evidence for activity-dependent changes occurring in inhibitory axons, in cultures as well as in vivo. Axons form many presynaptic terminals, which are dynamic structures sharing presynaptic material along the axonal shaft. We discuss how internal (e.g., vesicle sharing) and external factors (e.g., binding of cell adhesion molecules or secreted factors) may affect the formation and plasticity of inhibitory synapses.
    Frontiers in Cellular Neuroscience 11/2013; 7:219. DOI:10.3389/fncel.2013.00219 · 4.29 Impact Factor
Show more

Preview (2 Sources)

38 Reads
Available from