Activity-Dependent Proteolytic Cleavage of Neuroligin-1

Suzuki, Kenichi; Hayashi, Yasumasa; Nakahara, Soichiro; Kumazaki, Hiroshi; Prox, Johannes; Horiuchi, Keisuke; Zeng, Mingshuo; Tanimura, Shun; Nishiyama, Yoshitake; Osawa, Satoko; Sehara-Fujisawa, Atsuko; Säftig, Paul; Yokoshima, Satoshi; Fukuyama, Tohru; Matsuki, Norio; Koyama, Ryuta; Tomita, Taisuke; Iwatsubo, Takeshi

doi:10.1016/j.neuron.2012.10.003

Cited by 194 publications

(244 citation statements)

References 75 publications

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“…This indicated MMP and ADAM family proteases as candidate enzymes, a prediction consistent with the reported enzyme(s) responsible for Nlgn1 cleavage 17,18 and neural ADAM10 targets 19 . Active slice CM generated in the absence and presence of various protease inhibitors exhibited decreased neuroligin-3 shedding with MMP9 and ADAM10 inhibitors (Fig.…”

supporting

confidence: 85%

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Venkatesh

Tam

Woo

et al. 2017

Nature

404

374

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Summary High-grade gliomas (HGG) are a devastating group of cancers, representing the leading cause of brain tumor-related death in both children and adults. Therapies aimed at mechanisms intrinsic to the glioma cell have translated to only limited success; effective therapeutic strategies will need to also target elements of the tumor microenvironment that promote glioma progression. We recently demonstrated that neuronal activity robustly promotes the growth of a range of molecularly and clinically distinct HGG types, including adult glioblastoma (GBM), anaplastic oligodendroglioma, pediatric GBM, and diffuse intrinsic pontine glioma (DIPG)1. An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K-mTOR pathway1. However, neuroligin-3 necessity to glioma growth, proteolytic mechanism of secretion and further molecular consequences in glioma remain to be clarified. Here, we demonstrate a striking dependence of HGG growth on microenvironmental neuroligin-3, elucidate signaling cascades downstream of neuroligin-3 binding in glioma and determine a therapeutically targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric GBM, DIPG and adult GBM fail to grow in Nlgn3 knockout mice. Neuroligin-3 stimulates numerous oncogenic pathways, including early focal adhesion kinase activation upstream of PI3K-mTOR, and induces transcriptional changes including upregulation of numerous synapse-related genes in glioma cells. Neuroligin-3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors prevent release of neuroligin-3 into the tumor microenvironment and robustly block HGG xenograft growth. This work defines a promising strategy for targeting neuroligin-3 secretion, which could prove transformative for HGG therapy.

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supporting

confidence: 85%

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Venkatesh

Tam

Woo

et al. 2017

Nature

404

374

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“…In addition, in B6 mice, synaptic NLG1 protein level was also decreased by SD in the anterior forebrain, which could be more representative of NLG1 with B, given the absence of changes for the other variants. Indeed, recent data indicate that neuronal activity decreases NLG1 level at the synapse (25,42), and our findings suggest that this decrease mainly concerns the isoform containing insert B. NLG1 with B, the expression of which in the brain prevails over isoforms lacking B (19), is mostly localized at glutamatergic synapses and is specifically implicated in the interaction with presynaptic Neurexins (NRX) (19,29). Studies have shown that proper NMDAR function requires both the presence of NRX and NLG (21,43,44).…”

Section: Discussionmentioning

confidence: 53%

Neuroligin-1 links neuronal activity to sleep-wake regulation

Helou

Bélanger-Nelson

Freyburger

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

104

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Maintaining wakefulness is associated with a progressive increase in the need for sleep. This phenomenon has been linked to changes in synaptic function. The synaptic adhesion molecule Neuroligin-1 (NLG1) controls the activity and synaptic localization of N-methyl-Daspartate receptors, which activity is impaired by prolonged wakefulness. We here highlight that this pathway may underlie both the adverse effects of sleep loss on cognition and the subsequent changes in cortical synchrony. We found that the expression of specific Nlg1 transcript variants is changed by sleep deprivation in three mouse strains. These observations were associated with strainspecific changes in synaptic NLG1 protein content. Importantly, we showed that Nlg1 knockout mice are not able to sustain wakefulness and spend more time in nonrapid eye movement sleep than wild-type mice. These changes occurred with modifications in waking quality as exemplified by low theta/alpha activity during wakefulness and poor preference for social novelty, as well as altered delta synchrony during sleep. Finally, we identified a transcriptional pathway that could underlie the sleep/wake-dependent changes in Nlg1 expression and that involves clock transcription factors. We thus suggest that NLG1 is an element that contributes to the coupling of neuronal activity to sleep/wake regulation.ChIP | EEG | gene expression | sleep homeostasis | synaptic plasticity S leep is crucial for learning, memory, and other functions essential for proper functioning of the brain and body (1, 2). These functions have been associated with the sleep recovery process, which defines a level of pressure for sleep that increases with wakefulness and dissipates during sleep and that is reflected by changes in sleep intensity (3, 4). Sleep intensity is indexed by electroencephalographic (EEG) markers of neuronal synchrony in delta frequencies (1-4 Hz) measured during nonrapid eye movement (NREM) sleep (5). During wakefulness, mechanisms favoring desynchrony in the delta range predominate, and the brain can maintain cognition, whereas during sleep, events promoting network synchrony mostly take place with high delta activity thought to be permissive of recovery (3, 6). The sleep recovery process has been hypothesized to originate and contribute to the maintenance of both synaptic and network equilibrium (6-8). This notion is supported by the observation that specific plasticityrelated genes may be directly involved in regulating sleep need (9). Certain clock genes may also directly contribute, in a circadian-independent manner, to the sleep recovery process (5, 9). However, the mechanisms underlying the capacity and requirement of the brain to switch from an alert desynchronized state to an unconscious synchronized state remain elusive.Glutamate, the main excitatory neurotransmitter of the brain, can induce long-term modifications of synaptic transmission and, thus, changes in network connectivity. This is achieved mainly via glutamate's action on two types of receptors: N-methyl-D-aspa...

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“…In addition, it could facilitate synaptic disassembly. For example, removal of transsynaptic ligands by proteolytic cleavage, as recently reported for neuroligin-1 (Peixoto et al, 2012;Suzuki et al, 2012) and NGL-3 , might rapidly reduce the affinity of cis interactions and trigger the disassembly of adhesion protein complexes.…”

Section: Discussionmentioning

confidence: 87%

Trans-induced cis interaction in the tripartite NGL-1, netrin-G1, and LAR adhesion complex promotes excitatory synaptic development

Song

Lee

Prosselkov

et al. 2013

Journal of Cell Science

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SummaryThe initial contact between axons and dendrites at early neuronal synapses is mediated by surface adhesion molecules and is thought to induce synaptic maturation through the recruitment of additional synaptic proteins. The initiation of synaptic maturation should be tightly regulated to ensure that synaptic maturation occurs selectively at subcellular sites of axo-dendritic adhesion. However, the underlying mechanism is poorly understood. Here, we report that the initial trans-synaptic adhesion mediated by presynaptic netrin-G1 and postsynaptic NGL-1 (netrin-G1 ligand-1) induces a cis interaction between netrin-G1 and the receptor protein tyrosine phosphatase LAR (leukocyte antigen-related), and that this promotes presynaptic differentiation. We propose that trans-synaptic adhesions at early neuronal synapses trigger recruitment of neighboring adhesion molecules in a cis manner in order to couple initial axo-dendritic adhesion with synaptic differentiation.

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Activity-Dependent Proteolytic Cleavage of Neuroligin-1

Cited by 194 publications

References 75 publications

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

Neuroligin-1 links neuronal activity to sleep-wake regulation

Trans-induced cis interaction in the tripartite NGL-1, netrin-G1, and LAR adhesion complex promotes excitatory synaptic development

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