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Sarah T. South - One of the best experts on this subject based on the ideXlab platform.

  • chromosomal loss of 3q26 3 3q26 32 involving a partial neuroligin 1 deletion identified by genomic microarray in a child with microcephaly seizure disorder and severe intellectual disability
    American Journal of Medical Genetics Part A, 2012
    Co-Authors: Alison Millson, Danielle Lagrave, Leslie R Rowe, Mary Willis, Elaine Lyon, Sarah T. South
    Abstract:

    Neuroligin 1 (NLGN1) is one of five members of the neuroligin gene family and may represent a candidate gene for neurological disorders, as members of this family are involved in formation and remodeling of central nervous system synapses. NLGN1 is expressed predominantly in the central nervous system, where it dimerizes and then binds with β-neurexin to form a functional synapse. Mutations in neurexin 1 (NRXN1) as well as two other members of the neuroligin family, NLGN3 and NLGN4, have been associated with autism and mutations in NLGN4 have also been associated with intellectual disability, seizures, and EEG abnormalities. Genomic microarray is recommended for the detection of chromosomal gains or losses in patients with intellectual disability and multiple congenital anomalies. Results of uncertain significance are not uncommon. Parental studies can provide additional information by demonstrating that the imbalance is either de novo or inherited, and therefore is more or less likely to be causative of the clinical phenotype. However, the possibility that even inherited deletions and duplications may play a role in the phenotype of the proband cannot be excluded as many copy number variants associated with neurodevelopmental conditions show incomplete penetrance and may be inherited from an unaffected parent. Here, we report on a patient with a 2.2 Mb deletion at 3q26.3-3q26.32—encompassing the terminal end of NLGN1 and the entire NAALADL2 gene—detected by genomic microarray, and confirmed by FISH and real-time quantitative PCR. The same size deletion was subsequently found in her healthy, asymptomatic, adult mother. © 2011 Wiley Periodicals, Inc.

  • Chromosomal loss of 3q26.3-3q26.32, involving a partial neuroligin 1 deletion, identified by genomic microarray in a child with microcephaly, seizure disorder, and severe intellectual disability.
    American journal of medical genetics. Part A, 2011
    Co-Authors: Alison Millson, Danielle Lagrave, Mary J H Willis, Leslie R Rowe, Elaine Lyon, Sarah T. South
    Abstract:

    Neuroligin 1 (NLGN1) is one of five members of the neuroligin gene family and may represent a candidate gene for neurological disorders, as members of this family are involved in formation and remodeling of central nervous system synapses. NLGN1 is expressed predominantly in the central nervous system, where it dimerizes and then binds with β-neurexin to form a functional synapse. Mutations in neurexin 1 (NRXN1) as well as two other members of the neuroligin family, NLGN3 and NLGN4, have been associated with autism and mutations in NLGN4 have also been associated with intellectual disability, seizures, and EEG abnormalities. Genomic microarray is recommended for the detection of chromosomal gains or losses in patients with intellectual disability and multiple congenital anomalies. Results of uncertain significance are not uncommon. Parental studies can provide additional information by demonstrating that the imbalance is either de novo or inherited, and therefore is more or less likely to be causative of the clinical phenotype. However, the possibility that even inherited deletions and duplications may play a role in the phenotype of the proband cannot be excluded as many copy number variants associated with neurodevelopmental conditions show incomplete penetrance and may be inherited from an unaffected parent. Here, we report on a patient with a 2.2 Mb deletion at 3q26.3-3q26.32-encompassing the terminal end of NLGN1 and the entire NAALADL2 gene-detected by genomic microarray, and confirmed by FISH and real-time quantitative PCR. The same size deletion was subsequently found in her healthy, asymptomatic, adult mother.

Humsa S Venkatesh - One of the best experts on this subject based on the ideXlab platform.

  • targeting neuronal activity regulated neuroligin 3 dependency in high grade glioma
    Nature, 2017
    Co-Authors: Humsa S Venkatesh, Surya Nagaraja, Lydia T Tam, Pamelyn J Woo, Shawn M Gillespie, James Lennon, Damien Y Duveau, Patrick J Morris, Jean J Zhao, Craig J Thomas
    Abstract:

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

  • targeting neuronal activity regulated neuroligin 3 dependency for high grade glioma therapy
    bioRxiv, 2017
    Co-Authors: Humsa S Venkatesh, Surya Nagaraja, Lydia T Tam, Pamelyn J Woo, Shawn M Gillespie, James Lennon, Damien Y Duveau, Patrick J Morris, Jean J Zhao, Craig J Thomas
    Abstract:

    Neuronal activity promotes high-grade glioma (HGG) growth. An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule and glioma mitogen neuroligin-3 (NLGN3), but the therapeutic potential of targeting NLGN3 in glioma remains to be defined. We demonstrate a striking dependence of HGG growth on microenvironmental NLGN3 and determine a targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric glioblastoma, diffuse intrinsic pontine glioma and adult glioblastoma fail to grow in NLGN3 knockout mice. Glioma exposure to NLGN3 results in numerous signaling consequences, including early focal adhesion kinase activation upstream of PI3K-mTOR. NLGN3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. Administration of ADAM10 inhibitors robustly blocks HGG xenograft growth. This work defines the therapeutic potential of and a promising strategy for targeting NLGN3 secretion in the glioma microenvironment, which could prove transformative for treatment of HGG.

  • targeting neuronal activity regulated neuroligin 3 secretion for glioma therapy cci 001
    Neurology, 2017
    Co-Authors: Humsa S Venkatesh, Michelle Monje
    Abstract:

    Objective: To therapeutically target NLGN3 secretion in the glioma microenvironment. Background: We previously demonstrated that neuronal activity promotes high-grade glioma (HGG) growth. An important mechanism mediating this neural regulation of HGG growth is activity-dependent cleavage and secretion of the synaptic molecule and glioma mitogen neuroligin-3 (NLGN3) from cells in the microenvironment, but the enzyme mediating cleavage and the therapeutic potential of targeting NLGN3 in glioma remains to be defined. Design/Methods: To test the role of microenvironmental NLGN3 in HGG growth, patient-derived high-grade glioma cells (pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG)) were orthotopically xenografted to the frontal cortex or the pons of NLGN3 knock out or NLGN3 WT mice and tumor growth was assessed by in vivo bioluminescent imaging and by histological examination. The cellular source of secreted NLGN3 and the enzyme mediating cleavage were determined using genetically-engineered mouse models together with analysis of NLGN3 secretion from acute brain slices. Pharmacological inhibition of the enzyme identified as responsible for activity-dependent NLGN3 cleavage was tested as a therapeutic strategy in orthotopic xenograft models of pGBM and DIPG. Results: Here, we demonstrate a striking dependence of HGG growth on microenvironmental NLGN3 and determine a targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) fail to grow in NLGN3 knock out mice. NLGN3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. Administration of an ADAM10 inhibitor robustly blocks pGBM and DIPG xenograft growth via modulation of the tumor microenvironment. Conclusions: This work defines the therapeutic potential of and an effective strategy for targeting NLGN3 secretion in the glioma microenvironment. Targeting NLGN3 dependency using ADAM10 inhibitor therapy could prove transformative for treatment of HGG. Study Supported by: The National Institutes of Health (1R01NS092597) and the V Foundation. Disclosure: Dr. Venkatesh has nothing to disclose. Dr. Monje has nothing to disclose.

  • neuronal activity promotes glioma growth through neuroligin 3 secretion
    Cell, 2015
    Co-Authors: Humsa S Venkatesh, Tessa Johung, Viola Caretti, Alyssa Noll, Yujie Tang, Surya Nagaraja, Erin M Gibson, Christopher Mount, Jai S Polepalli, Siddhartha Mitra
    Abstract:

    Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth.

Enriqueta Tristanclavijo - One of the best experts on this subject based on the ideXlab platform.

  • a truncating mutation in alzheimer s disease inactivates neuroligin 1 synaptic function
    Neurobiology of Aging, 2015
    Co-Authors: Enriqueta Tristanclavijo, Rafael J Camachogarcia, Estefania Robleslanuza, Amalia Martinezmir, Agustín Ruiz, Christine Van Broeckhoven, Isabel Hernández, Francisco G. Scholl
    Abstract:

    Neuroligins (NLs) are cell-adhesion proteins that regulate synapse formation and function. Neuroligin 1 (NL1) promotes the formation of glutamatergic synapses and mediates long-term potentiation in mouse models. Thus, altered NL1 function could mediate the synaptic and memory deficits associated with Alzheimer's disease (AD). Here, we describe a frameshift mutation, c.875_876insTT, in the neuroligin 1 gene (NLGN1) in a patient with AD and familial history of AD. The insertion generates a premature stop codon in the extracellular domain of NL1 (p.Thr271fs). Expression of mutant NL1 shows accumulation of truncated NL1 proteins in the endoplasmic reticulum. In hippocampal neurons, the p.Thr271fs mutation abolishes the ability of NL1 to promote the formation of glutamatergic synapses. Our data support a role for inactivating mutations in NLGN1 in AD. Previous studies have reported rare mutations in X-linked NLGNL3 and NLGNL4 genes in patients with autism, which result in the inactivation of the mutant alleles. Therefore, together with a role in neurodevelopmental disorders, altered NL function could underlie the molecular mechanisms associated with brain diseases in the elderly.

Toru Takumi - One of the best experts on this subject based on the ideXlab platform.

  • functional significance of rare neuroligin 1 variants found in autism
    PLOS Genetics, 2017
    Co-Authors: Moe Nakanishi, Jun Nomura, Xiao Ji, Kota Tamada, Takashi Arai, Eiki Takahashi, Maja Bucan, Toru Takumi
    Abstract:

    Genetic mutations contribute to the etiology of autism spectrum disorder (ASD), a common, heterogeneous neurodevelopmental disorder characterized by impairments in social interaction, communication, and repetitive and restricted patterns of behavior. Since neuroligin3 (NLGN3), a cell adhesion molecule at the neuronal synapse, was first identified as a risk gene for ASD, several additional variants in NLGN3 and NLGN4 were found in ASD patients. Moreover, synaptopathies are now known to cause several neuropsychiatric disorders including ASD. In humans, NLGNs consist of five family members, and neuroligin1 (NLGN1) is a major component forming a complex on excitatory glutamatergic synapses. However, the significance of NLGN1 in neuropsychiatric disorders remains unknown. Here, we systematically examine five missense variants of NLGN1 that were detected in ASD patients, and show molecular and cellular alterations caused by these variants. We show that a novel NLGN1 Pro89Leu (P89L) missense variant found in two ASD siblings leads to changes in cellular localization, protein degradation, and to the impairment of spine formation. Furthermore, we generated the knock-in P89L mice, and we show that the P89L heterozygote mice display abnormal social behavior, a core feature of ASD. These results, for the first time, implicate rare variants in NLGN1 as functionally significant and support that the NLGN synaptic pathway is of importance in the etiology of neuropsychiatric disorders.

  • In silico investigation of NLGN1 variants observed in patients with ASD.
    2017
    Co-Authors: Moe Nakanishi, Jun Nomura, Kota Tamada, Takashi Arai, Eiki Takahashi, Maja Bućan, Toru Takumi
    Abstract:

    (A) Ribbon diagram of the extracellular part of the mouse NLGN1 dimer viewed from the side, based on Protein Data Bank (PDB) entry 3B3Q. The dotted line shows the NLGN1 region for which crystal structure is unavailable. Amino-acid numberings of mouse NLGN1 (human NLGN1) are indicated. The variants assessed in this study are shown in red. The gray box indicates the location of a proline-rich loop of NLGN1. (B) Ribbon diagram of the NLGN1-NRXN1β complex, viewed from the post-synaptic membrane with variants. (C) Enlarged image of the proline-rich loop structure of NLGN1 in which P89 is located (shown in light blue). Previously identified NLGN4 missense variants (G84R, R87W, and G99S) found in ASD are also indicated. (D) The protein alignment of the NLGN1-4 family. The highly conserved P89 residue, mutated in ASD patients, is boxed in red, and pathogenic NLGN4 variants, localized in the same loop, are shown as blue arrows.

  • Pathogenic NLGN1 variants exhibit abnormal sub-localization and expression.
    2017
    Co-Authors: Moe Nakanishi, Jun Nomura, Kota Tamada, Takashi Arai, Eiki Takahashi, Maja Bućan, Toru Takumi
    Abstract:

    (A) Fluorescence images of COS7 cells transfected WT or mutant NLGN1 with HA-tag. Endoplasmic reticulum (ER) was stained with calnexin. Three pathogenic variants (P89L, L269P, and G288E) were trapped in ER, and failed to traffic the plasma membrane. Scale bar indicates 10 μm. (B) Representative images of western blots of cell lysates from COS7 cells transfected with HA-tagged NLGN1. NLGN1 was detected by anti-HA tag. The expected molecular weight for the NLGN1: glycosylated mature NLGN1 (~110 kDa), non-glycosylated immature NLGN1 (~100 kDa). (C) Quantitative analysis of the western blots for total (left) and glycosylated (right) NLGN1. The expression of NLGN1 variants is normalized to the corresponding β-actin. NLGN1 variants observed in ASD subjects showed decreased expression level compared to WT. Data represents mean ± S.E.M. of four samples from three independent experiments (one-way ANOVA followed by Tukey-Kramer’s multiple comparisons test, *p

  • Impaired spine induction by NLGN1 variants observed in patients with ASD.
    2017
    Co-Authors: Moe Nakanishi, Jun Nomura, Kota Tamada, Takashi Arai, Eiki Takahashi, Maja Bućan, Toru Takumi
    Abstract:

    (A) Representative fluorescence images of hippocampal neurons (DIV14) co-transfected with negative control, WT, and non-pathogenic NLGN1 or pathogenic NLGN1 variants with GFP expression vector. NLGN1 expression of pathogenic variants (P89L, L269P, G288E, and H786Y) was decreased compared to others. (B) Representative images of spines from neurons transfected with negative control, WT, and non-pathogenic NLGN1 or pathogenic variants of NLGN1. (C) Quantification of the number of spines. Spine number in dendrite was significantly lower in four pathogenic variants (P89L, L269P, G288E, and H786Y) compared to WT, and no significant differences between GFP-transfected control and these four variants were observed. Data represent mean ± S.E.M. (*p

Stephane J Baudouin - One of the best experts on this subject based on the ideXlab platform.

  • rescue of oxytocin response and social behaviour in a mouse model of autism
    Nature, 2020
    Co-Authors: Hanna Hornberg, Enrique Perezgarci, Dietmar Schreiner, Laetitia Hatstattburkle, Fulvio Magara, Stephane J Baudouin, Alex Matter, Kassoum Nacro, Eline Pechovrieseling, Peter Scheiffele
    Abstract:

    A fundamental challenge in developing treatments for autism spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of cases1-3. Subsets of risk genes can be grouped into functionally related pathways, most prominently those involving synaptic proteins, translational regulation, and chromatin modifications. To attempt to minimize this genetic complexity, recent therapeutic strategies have focused on the neuropeptides oxytocin and vasopressin4-6, which regulate aspects of social behaviour in mammals7. However, it is unclear whether genetic risk factors predispose individuals to autism as a result of modifications to oxytocinergic signalling. Here we report that an autism-associated mutation in the synaptic adhesion molecule NLGN3 results in impaired oxytocin signalling in dopaminergic neurons and in altered behavioural responses to social novelty tests in mice. Notably, loss of NLGN3 is accompanied by a disruption of translation homeostasis in the ventral tegmental area. Treatment of NLGN3-knockout mice with a new, highly specific, brain-penetrant inhibitor of MAP kinase-interacting kinases resets the translation of mRNA and restores oxytocin signalling and social novelty responses. Thus, this work identifies a convergence between the genetic autism risk factor NLGN3, regulation of translation, and oxytocinergic signalling. Focusing on such common core plasticity elements might provide a pragmatic approach to overcoming the heterogeneity of autism. Ultimately, this would enable mechanism-based stratification of patient populations to increase the success of therapeutic interventions.

  • evidence for a contribution of the NLGN3 cyfip1 fmr1 pathway in the pathophysiology of autism spectrum disorders
    Neuroscience, 2019
    Co-Authors: Monika Sledziowska, James C Galloway, Stephane J Baudouin
    Abstract:

    Autism Spectrum Disorders (ASD) are characterized by heterogeneity both in their presentation and their genetic aetiology. In order to discover points of convergence common to different cases of ASD, attempts were made to identify the biological pathways genes associated with ASD contribute to. Many of these genes were found to play a role in neuronal and synaptic development and function. Among these genes are FMR1, CYFIP1 and NLGN3, all present at the synapse and reliably linked to ASD. In this review, we evaluate the evidence for the contribution of these genes to the same biological pathway responsible for the regulation of structural and physiological plasticity. Alterations in dendritic spine density and turnover, as well as long-term depression (LTD), were found in mouse models of mutations of all three genes. This overlap in the phenotypes associated with these mouse models likely arises from the molecular interaction between the protein products of FMR1, CYFIP1, and NLG3. A number of other proteins linked to ASD are also likely to participate in these pathways, resulting in further downstream effects. Overall, a synaptic pathway centered around FMR1, CYFIP1, and NLG3 is likely to contribute to the phenotypes associated with structural and physiological plasticity characteristic of ASD.

  • male and female mice lacking neuroligin 3 modify the behavior of their wild type littermates
    eNeuro, 2017
    Co-Authors: Shireene Kalbassi, Sven O Bachmann, Ellen Cross, Victoria H Roberton, Stephane J Baudouin
    Abstract:

    In most mammals, including humans, the postnatal acquisition of normal social and nonsocial behavior critically depends on interactions with peers. Here we explore the possibility that mixed-group housing of mice carrying a deletion of NLGN3, a gene associated with autism spectrum disorders, and their wild-type littermates induces changes in each other's behavior. We have found that, when raised together, male NLGN3 knockout mice and their wild-type littermates displayed deficits in sociability. Moreover, social submission in adult male NLGN3 knockout mice correlated with an increase in their anxiety. Re-expression of NLGN3 in parvalbumin-expressing cells in transgenic animals rescued their social behavior and alleviated the phenotype of their wild-type littermates, further indicating that the social behavior of NLGN3 knockout mice has a direct and measurable impact on wild-type animals' behavior. Finally, we showed that, unlike male mice, female mice lacking NLGN3 were insensitive to their peers' behavior but modified the social behavior of their littermates. Altogether, our findings show that the environment is a critical factor in the development of behavioral phenotypes in transgenic and wild-type mice. In addition, these results reveal that the social environment has a sexually dimorphic effect on the behavior of mice lacking NLGN3, being more influential in males than females.