Deletion of the Neuron-Specific Protein Delta-Catenin Leads to Severe Cognitive and Synaptic Dysfunction

Israely, Inbal; Costa, Rui M.; Xie, Cui Wei; Silva, Alcino J.; Kosik, Kenneth S.; Liu, Xin

doi:10.1016/j.cub.2004.08.065

Cited by 137 publications

(162 citation statements)

References 28 publications

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“…This suggests that cadherins can themselves contribute to spine and synapse plasticity. Because knock-out of ␦-catenin (NPRAP) leads to specific neural deficits resembling cri du chat syndrome, a form of mental retardation Israely et al, 2004), disruption of the interactions described here may have a role in neurological disease.…”

Section: Control Of Cell Adhesionmentioning

confidence: 99%

Synaptic Anchorage of AMPA Receptors by Cadherins through Neural Plakophilin-Related Arm Protein–AMPA Receptor-Binding Protein Complexes

Silverman¹,

Restituito²,

Lü³

et al. 2007

J. Neurosci.

113

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Cadherins function in the adhesion of presynaptic and postsynaptic membranes at excitatory synapses. Here we show that the cadherinassociated protein neural plakophilin-related arm protein (NPRAP; also called ␦-catenin) binds via a postsynaptic density-95 (PSD-95)/ discs large/zona occludens-1 (PDZ) interaction to AMPA receptor (AMPAR)-binding protein (ABP) and the related glutamate receptor (GluR)-interacting protein (GRIP), two multi-PDZ proteins that bind the GluR2 and GluR3 AMPAR subunits. The resulting cadherin-NPRAP-ABP/GRIP complexes serve as anchorages for AMPARs. Exogenous NPRAP that was bound to cadherins at adherens junctions of Madin-Darby canine kidney cells recruited ABP from the cytosol to form cadherin-NPRAP-ABP complexes, dependent on NPRAP interaction with the ABP PDZ domain 2. The cadherin-NPRAP-ABP complexes also bound GluR2. In cultured hippocampal neurons, dominant-negative mutants of NPRAP designed to disrupt tethering of ABP to NPRAP-cadherin complexes reduced surface levels of endogenous GluR2, indicating that interaction with cadherin-NPRAP-ABP complexes stabilized GluR2 at the neuronal plasma membrane. Cadherins, NPRAP, GRIP, and GluR2 copurified in the fractionation of synaptosomes and the postsynaptic density, two fractions enriched in synaptic proteins. Furthermore, synaptosomes contain NPRAP-GRIP complexes, and NPRAP localizes with the postsynaptic marker PSD-95 and with AMPARs and GRIP at spines of hippocampal neurons. Thus, tethering is likely to take place at synaptic or perisynaptic sites. NPRAP also binds PSD-95, which is a scaffold for NMDA receptors, for AMPARs in complexes with auxiliary subunits, the TARPs (transmembrane AMPA receptor regulator proteins), and for adhesion molecules. Thus, the interaction of scaffolding proteins with cadherin-NPRAP complexes may anchor diverse signaling and adhesion molecules at cadherins.

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Section: Control Of Cell Adhesionmentioning

confidence: 99%

Synaptic Anchorage of AMPA Receptors by Cadherins through Neural Plakophilin-Related Arm Protein–AMPA Receptor-Binding Protein Complexes

Silverman¹,

Restituito²,

Lü³

et al. 2007

J. Neurosci.

113

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“…Depolarization of neurons in culture leads to an accumulation of β-catenin in dendritic spines, where it modifies synaptic strength by interacting with cadherins 79 . Mice lacking the neuron-specific Δ-catenin exhibit deficits in CA1 LTP and hippocampusdependent memory tasks 133 , and loss of αN-catenin results in long-term memory defects 134 .…”

Section: Author Manuscriptmentioning

confidence: 99%

Cell adhesion molecules: signalling functions at the synapse

2007

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Many cell adhesion molecules are localized at synaptic sites in neuronal axons and dendrites. These molecules bridge pre-and postsynaptic specializations but do far more than simply provide a mechanical link between cells. In this review, we will discuss the roles these proteins have during development and at mature synapses. Synaptic adhesion proteins participate in the formation, maturation, function and plasticity of synaptic connections. Together with conventional synaptic transmission mechanisms, these molecules are an important element in the trans-cellular communication mediated by synapses.CNS synapses are specialized sites of cell-cell contact that mediate the transmission of information between neurons. Synapses are a key site of regulation within neural networks and are characterized by multi-protein complexes arranged at tightly apposed pre-and postsynaptic terminals. Communication between neurons at synapses is mediated primarily by neurotransmitter release and by the gating of postsynaptic receptor ion channels, but a growing body of evidence indicates that signalling is also mediated by adhesion molecules that interact in a homo-or heterophilic fashion across the synaptic cleft. As at other cell-cell junctions, such as epithelial tight junctions or the immune synapse, research in a variety of neuronal subtypes has shown that synaptically localized cell adhesion molecules (SAMs) are not merely static structural components but are often dynamic regulators of synapse function. When pairs of SAMs interact, they can induce the formation of new synapses or modulate the function of existing synapses through signalling cascades or secondary protein-protein interactions. Numerous studies indicate that interactions between specific SAMs can control synapse formation, regulate dendritic spine morphology, modify synaptic receptor function and modulate synaptic plasticity. So, SAMs can mediate physical interactions between cells and act at multiple steps in the life of a synapse (FIG. 1).Here, we focus on well-studied classes of SAMs that have roles at both developing and mature synapses, namely neurexins and neuroligins, EphBs and ephrin-Bs, immunoglobulinCorrespondence to: M.B.D. dalva@mail.med.upenn.edu. Competing interests statementThe authors declare no competing financial interests. Note added in proofIn a recently published manuscript, Futai et al. 144 demonstrate that trans-synaptic β-neurexin-neuroligin interactions can modulate presynaptic function. The authors show that overexpression or knockdown of PSD-95 in the postsynaptic cell modulates presynaptic release probability, and that these effects are blocked when trans-synaptic β-neurexin-neuroligin signalling is disrupted. This paper provides further evidence that SAMs act to regulate synaptic function. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript (Ig)-containing cell adhesion molecules and cadherins. We discuss the ways in which these proteins seem to control discrete aspects of synaptic develop...

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“…Many of these proteins are enriched in the postsynaptic density, where they participate in the regulation of dendritic spine morphology and associate with the cytoskeleton. For instance, synaptopodin 44 , synGAP 19 , and SH3 and multiple ankyrin repeat domains protein 2 (SHANK2) 49 are crucial for the normal formation of dendritic spine apparatuses [51][52][53] , and synaptopodin and δ-catenin have important roles in learning and memory 51,54 .…”

Section: Synaptic Proteins and Neuronal Communicationmentioning

confidence: 99%

Chemical approaches to understanding O-GlcNAc glycosylation in the brain

2008

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O -GlcNAc glycosylation is a unique, dynamic form of glycosylation found on intracellular proteins of all multicellular organisms. Studies suggest that O-GlcNAc represents a key regulatory modification in the brain, contributing to transcriptional regulation, neuronal communication and neurodegenerative disease. Recently, several new chemical tools have been developed to detect and study the modification, including chemoenzymatic tagging methods, quantitative proteomics strategies and small-molecule inhibitors of O-GlcNAc enzymes. Here we highlight some of the emerging roles for O-GlcNAc in the nervous system and describe how chemical tools have significantly advanced our understanding of the scope, functional significance and cellular dynamics of this modification.O-GlcNAc glycosylation, the covalent attachment of β-N-acetylglucosamine to serine or threonine residues of proteins, is an unusual form of protein glycosylation 1 (Fig. 1). Unlike other types of glycosylation, this single-sugar modification occurs on intracellular proteins and is not elaborated further into complex glycans. The O-GlcNAc transferase (OGT) enzyme is a soluble protein that is found in the cytosol, nucleus and mitochondria 2 , rather than in the endoplasmic reticulum or Golgi. The dynamics of O-GlcNAc are also unique among sugar modifications, being cycled on a shorter time scale than protein turnover 3 . Thus, in many respects O-GlcNAc is more akin to phosphorylation than to conventional forms of glycosylation. Several reviews have described the roles of O-GlcNAc in cellular processes, such as transcription 2,4 , the stress response 5,6 , apoptosis 7,8 , signal transduction 2,9 , glucose sensing 5,10 and proteasomal degradation 5 . Only a few reviews have highlighted the importance of O-GlcNAc glycosylation in the nervous system, and those reports have focused on its potential impact on neurodegenerative diseases 11,12 . However, several lines of evidence suggest that O-GlcNAc has crucial roles in both neuronal function and dysfunction. The enzymes responsible for the modification are most highly expressed in the brain 13,14 and are enriched at neuronal synapses 15,16 . Neuron-specific deletion of the OGT gene in mice leads to abnormal development and locomotor defects, resulting in neonatal death 17 . The O-GlcNAc modification is abundant in the brain and present on many proteins important for transcription, neuronal signaling and synaptic plasticity, such as cAMPresponsive element binding protein (CREB) 18 , synaptic Ras GTPase-activating protein (synGAP) 19 and β-amyloid precursor protein (APP) 20 . An intriguing interplay between OGlcNAc glycosylation and phosphorylation has been observed in cerebellar neurons, wherein activation of certain kinase pathways reduces O-GlcNAc levels on cytoskeleton-

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Deletion of the Neuron-Specific Protein Delta-Catenin Leads to Severe Cognitive and Synaptic Dysfunction

Cited by 137 publications

References 28 publications

Synaptic Anchorage of AMPA Receptors by Cadherins through Neural Plakophilin-Related Arm Protein–AMPA Receptor-Binding Protein Complexes

Synaptic Anchorage of AMPA Receptors by Cadherins through Neural Plakophilin-Related Arm Protein–AMPA Receptor-Binding Protein Complexes

Cell adhesion molecules: signalling functions at the synapse

Chemical approaches to understanding O-GlcNAc glycosylation in the brain

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