The Experts below are selected from a list of 2112 Experts worldwide ranked by ideXlab platform
Elizabeth M Tunbridge - One of the best experts on this subject based on the ideXlab platform.
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unraveling mechanisms of patient specific NRXN1 mutations in neuropsychiatric diseases using human induced pluripotent stem cells
2020Co-Authors: Alejandro De Los Angeles, Elizabeth M TunbridgeAbstract:Rare heterozygous deletions in the neurexin 1 (NRXN1) gene robustly increase an individual's risk of developing neurological and psychiatric disorders. However, the molecular bases by which different mutations result in different clinical presentations, with variable penetrance, are unknown. To better understand the molecular and cellular consequences of heterozygous NRXN1 mutations, Flaherty and colleagues studied how patient mutations influence the NRXN1 isoform repertoire and neuronal phenotypes using induced pluripotent stem (iPS) cells. Advancing from disease association to mechanistic insights, the authors provide insight into how patient mutations might impinge on neuronal function. This research highlights the value of iPS cells for elucidating otherwise elusive links between molecular and neuronal function. In addition, they provide further evidence of the importance of alternative splicing in the pathophysiology of neuropsychiatric diseases.
Peter Scheiffele - One of the best experts on this subject based on the ideXlab platform.
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sam68 regulates neuronal activity dependent alternative splicing of neurexin 1
2011Co-Authors: Takatoshi Iijima, Harald Witte, Yoko Hannoiijima, Timo Glatter, Stephane Richard, Peter ScheiffeleAbstract:The assembly of synapses and neuronal circuits relies on an array of molecular recognition events and their modification by neuronal activity. Neurexins are a highly polymorphic family of synaptic receptors diversified by extensive alternative splicing. Neurexin variants exhibit distinct isoform-specific biochemical interactions and synapse assembly functions, but the mechanisms governing splice isoform choice are not understood. We demonstrate that NRXN1 alternative splicing is temporally and spatially controlled in the mouse brain. Neuronal activity triggers a shift in NRXN1 splice isoform choice via calcium/calmodulin-dependent kinase IV signaling. Activity-dependent alternative splicing of NRXN1 requires the KH-domain RNA-binding protein SAM68 that associates with RNA response elements in the NRXN1 pre-mRNA. Our findings uncover SAM68 as a key regulator of dynamic control of NRXN1 molecular diversity and activity-dependent alternative splicing in the central nervous system.
Amanda J Law - One of the best experts on this subject based on the ideXlab platform.
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neurexin 1 NRXN1 splice isoform expression during human neocortical development and aging
2016Co-Authors: Aaron K Jenkins, Clare Paterson, Yanhong Wang, Thomas M Hyde, Joel E Kleinman, Amanda J LawAbstract:Neurexin 1 (NRXN1), a presynaptic cell adhesion molecule, is implicated in several neurodevelopmental disorders characterized by synaptic dysfunction including autism, intellectual disability and schizophrenia. To gain insight into NRXN1's involvement in human cortical development we used quantitative real-time PCR to examine the expression trajectories of NRXN1, and its predominant isoforms, NRXN1-α and NRXN1-β, in prefrontal cortex from fetal stages to aging. In addition, we investigated whether prefrontal cortical expression levels of NRXN1 transcripts are altered in schizophrenia or bipolar disorder in comparison with non-psychiatric control subjects. We observed that all three NRXN1 transcripts were highly expressed during human fetal cortical development, markedly increasing with gestational age. In the postnatal dorsolateral prefrontal cortex, expression levels were negatively correlated with age, peaking at birth until ~3 years of age, after which levels declined markedly to be stable across the lifespan. NRXN1-β expression was modestly but significantly elevated in the brains of patients with schizophrenia compared with non-psychiatric controls, whereas NRXN1-α expression was increased in bipolar disorder. These data provide novel evidence that NRXN1 expression is highest in human dorsolateral prefrontal cortex during critical developmental windows relevant to the onset and diagnosis of a range of neurodevelopmental disorders, and that NRXN1 expression may be differentially altered in neuropsychiatric disorders.
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Identification of Candidate Single-Nucleotide Polymorphisms in NRXN1 Related to Antipsychotic Treatment Response in Patients with Schizophrenia
2014Co-Authors: Aaron Jenkins, José A Apud, Fengyu Zhang, Heather Decot, Daniel R Weinberger, Amanda J LawAbstract:Neurexins are presynaptic neuronal adhesion molecules that interact with postsynaptic neuroligins to form an inter-synaptic complex required for synaptic specification and efficient neurotransmission. Deletions and point mutations in the neurexin 1 (NRXN1) gene are associated with a broad spectrum of neuropsychiatric and neurodevelopmental disorders, including autism, intellectual disability, epilepsy, developmental delay, and schizophrenia. Recently, small nucleotide polymorphisms in NRXN1 have been associated with antipsychotic drug response in patients with schizophrenia. Based on previous suggestive evidence of an impact on clozapine response in patients with schizophrenia, we conducted an association study of NRXN1 polymorphisms (rs12467557 and rs10490162) with antipsychotic treatment response in 54 patients with schizophrenia in a double blind, placebo-controlled NIMH inpatient crossover trial and examined for association with risk for schizophrenia in independent case-control and family-based clinical cohorts. Pharmacogenetic analysis in the placebo controlled trial revealed significant association of rs12467557and rs10490162 with drug response, whereby individuals homozygous for the A allele, at either SNP, showed significant improvement in positive symptoms, general psychopathology, thought disturbance, and negative symptoms, whereas patients carrying the G allele showed no overall response. Although we did not find evidence of the same NRXN1 SNPs being associated with results of the NIMH sponsored CATIE trial, other SNPs showed weakly positive signals. The family and case-control analyses for schizophrenia risk were negative. Our results provide confirmatory evidence of genetically determined differences in drug response in patients with schizophrenia related to NRXN1 variation. Furthermore, these findings potentially implicate NRXN1 in the therapeutic actions of antipsychotic drugs.
Keimpe D Wierda - One of the best experts on this subject based on the ideXlab platform.
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sorcs1 mediated sorting in dendrites maintains neurexin axonal surface polarization required for synaptic function
2019Co-Authors: Luis F Ribeiro, Ben Verpoort, Julie Nys, Kristel M Vennekens, Keimpe D WierdaAbstract:The pre- and postsynaptic membranes comprising the synaptic junction differ in protein composition. The membrane trafficking mechanisms by which neurons control surface polarization of synaptic receptors remain poorly understood. The sorting receptor Sortilin-related CNS expressed 1 (SorCS1) is a critical regulator of trafficking of neuronal receptors, including the presynaptic adhesion molecule neurexin (Nrxn), an essential synaptic organizer. Here, we show that SorCS1 maintains a balance between axonal and dendritic Nrxn surface levels in the same neuron. Newly synthesized NRXN1α traffics to the dendritic surface, where it is endocytosed. Endosomal SorCS1 interacts with the Rab11 GTPase effector Rab11 family-interacting protein 5 (Rab11FIP5)/Rab11 interacting protein (Rip11) to facilitate the transition of internalized NRXN1α from early to recycling endosomes and bias NRXN1α surface polarization towards the axon. In the absence of SorCS1, NRXN1α accumulates in early endosomes and mispolarizes to the dendritic surface, impairing presynaptic differentiation and function. Thus, SorCS1-mediated sorting in dendritic endosomes controls Nrxn axonal surface polarization required for proper synapse development and function.
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sorcs1 mediated sorting in dendrites maintains neurexin axonal surface polarization required for synaptic function
2019Co-Authors: Luis F Ribeiro, Ben Verpoort, Julie Nys, Kristel M Vennekens, Keimpe D Wierda, Joris De WitAbstract:Abstract The pre- and postsynaptic membranes comprising the synaptic junction differ in protein composition. The membrane trafficking mechanisms by which neurons control surface polarization of synaptic receptors remain poorly understood. The sorting receptor SorCS1 is a critical regulator of trafficking of neuronal receptors, including the presynaptic adhesion molecule neurexin (Nrxn), an essential synaptic organizer. Here, we show that SorCS1 maintains a balance between axonal and dendritic Nrxn surface levels in the same neuron. Newly synthesized NRXN1α traffics to the dendritic surface, where it is endocytosed. Endosomal SorCS1 interacts with the Rab11 effector protein Rab11FIP5/Rip11 to facilitate the transition of internalized NRXN1α from early to recycling endosomes and bias NRXN1α surface polarization toward the axon. In the absence of SorCS1, NRXN1α accumulates in early endosomes and mis-polarizes to the dendritic surface, impairing presynaptic differentiation and function. Thus, SorCS1-mediated sorting in dendritic endosomes controls Nrxn axonal surface polarization required for proper synapse development and function.
Tomoyuki Yoshida - One of the best experts on this subject based on the ideXlab platform.
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functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia
2020Co-Authors: Kanako Ishizuka, Tomoyuki Yoshida, Takeshi Kawabata, Ayako Imai, Hisashi Mori, Hiroki Kimura, Toshiya Inada, Yuko Okahisa, Jun Egawa, Masahide UsamiAbstract:Rare genetic variants contribute to the etiology of both autism spectrum disorder (ASD) and schizophrenia (SCZ). Most genetic studies limit their focus to likely gene-disrupting mutations because they are relatively easier to interpret their effects on the gene product. Interpretation of missense variants is also informative to some pathophysiological mechanisms of these neurodevelopmental disorders; however, their contribution has not been elucidated because of relatively small effects. Therefore, we characterized missense variants detected in NRXN1, a well-known neurodevelopmental disease-causing gene, from individuals with ASD and SCZ. To discover rare variants with large effect size and to evaluate their role in the shared etiopathophysiology of ASD and SCZ, we sequenced NRXN1 coding exons with a sample comprising 562 Japanese ASD and SCZ patients, followed by a genetic association analysis in 4273 unrelated individuals. Impact of each missense variant detected here on cell surface expression, interaction with NLGN1, and synaptogenic activity was analyzed using an in vitro functional assay and in silico three-dimensional (3D) structural modeling. Through mutation screening, we regarded three ultra-rare missense variants (T737M, D772G, and R856W), all of which affected the LNS4 domain of NRXN1α isoform, as disease-associated variants. Diagnosis of individuals with T737M, D772G, and R856W was 1ASD and 1SCZ, 1ASD, and 1SCZ, respectively. We observed the following phenotypic and functional burden caused by each variant. (i) D772G and R856W carriers had more serious social disabilities than T737M carriers. (ii) In vitro assay showed reduced cell surface expression of NRXN1α by D772G and R856W mutations. In vitro functional analysis showed decreased NRXN1α-NLGN1 interaction of T737M and D772G mutants. (iii) In silico 3D structural modeling indicated that T737M and D772G mutations could destabilize the rod-shaped structure of LNS2-LNS5 domains, and D772G and R856W could disturb N-glycan conformations for the transport signal. The combined data suggest that missense variants in NRXN1 could be associated with phenotypes of neurodevelopmental disorders beyond the diagnosis of ASD and/or SCZ.
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in situ screening for postsynaptic cell adhesion molecules during synapse formation
2017Co-Authors: Takeshi Uemura, Misato Yasumura, Tomoko Shiroshima, Tomoyuki Yoshida, Yuko Fukata, Masaki Fukata, Asami Maeda, Takashi ShimadaAbstract:: Neuronal synapse formation is regulated by pre- and postsynaptic cell adhesion molecules. Presynaptic neurexins (NRXNs) and receptor protein tyrosine phosphatases (RPTPs; PTPδ, PTPσ and LAR in mammals) can induce postsynaptic differentiation through the interaction with various postsynaptic cell adhesion molecules. Here, we developed a novel in situ screening method to identify postsynaptic membranous proteins involved in synaptogenesis. Magnetic beads coated with the extracellular domains of NRXN1β(-S4) and PTPδ-A6 variants preferentially induced excitatory postsynaptic differentiation on the beads' surface when co-cultured with cortical neurons. After inducing postsynaptic sites on these beads, protein complexes including NRXN1β(-S4)/PTPδ-A6 and their ligands on the neuronal membrane were chemically cross-linked and purified using a magnetic separator. Liquid chromatography-tandem mass spectrometry analysis of the complexes revealed two types of postsynaptic ligands for NRXN1β(-S4) and PTPδ-A6, one has an activity to induce presynaptic differentiation in a trans manner, whereas the other has no such activity. These results suggest that synapse formation is regulated by the interplay between presynaptic NRXN/PTPδ and their postsynaptic ligands with functionally different impacts on pre- and postsynaptic differentiation. Thus, our in situ screening method for identifying synapse-organizing complexes will help to understand the molecular basis for elaborate neuronal networks.
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trans synaptic interaction of glurδ2 and neurexin through cbln1 mediates synapse formation in the cerebellum
2010Co-Authors: Takeshi Uemura, Misato Yasumura, Tomoyuki Yoshida, Tomonori Takeuchi, Moonjin Ra, Ryo Taguchi, Kenji Sakimura, Masayoshi MishinaAbstract:Summary Elucidation of molecular mechanisms that regulate synapse formation is required for the understanding of neural wiring, higher brain functions, and mental disorders. Despite the wealth of in vitro information, fundamental questions about how glutamatergic synapses are formed in the mammalian brain remain unanswered. Glutamate receptor (GluR) δ2 is essential for cerebellar synapse formation in vivo. Here, we show that the N-terminal domain (NTD) of GluRδ2 interacts with presynaptic neurexins (NRXNs) through cerebellin 1 precursor protein (Cbln1). The synaptogenic activity of GluRδ2 is abolished in cerebellar primary cultures from Cbln1 knockout mice and is restored by recombinant Cbln1. Knockdown of NRXNs in cerebellar granule cells also hinders the synaptogenic activity of GluRδ2. Both the NTD of GluRδ2 and the extracellular domain of NRXN1β suppressed the synaptogenic activity of Cbln1 in cerebellar primary cultures and in vivo. These results suggest that GluRδ2 mediates cerebellar synapse formation by interacting with presynaptic NRXNs through Cbln1.
