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Results for “Synaptic adhesion protein”

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PubMed2025

ELFN1 deficiency: The mechanistic basis and phenotypic spectrum of a neurodevelopmental disorder with epilepsy.

PURPOSE: Synaptic communication deficits are central to many neurodevelopmental disorders. However, for rare monogenic conditions, these disorders remain poorly defined, with limited understanding of their molecular etiology. A homozygous frameshift variant in the synaptic cell adhesion molecule ELFN1 was reported in a family with 3 affected siblings with epileptic encephalopathy, alongside a missense variant of uncertain significance in a cohort study involving a family with intellectual disability. Therefore, we sought to evaluate the role and mechanism of biallelic ELFN1 variants in disease pathogenesis. METHODS: We describe 8 newly identified individuals from 5 unrelated families, all carrying homozygous ELFN1 variants, including frameshift and in-frame deletions. By integrating data from these cases with clinical details from 6 previously reported individuals, we delineate the phenotypic spectrum associated with ELFN1 variants. RESULTS: Clinical features include varying degrees of developmental delay/intellectual disability, epilepsy, and movement disorders. Molecular investigations reveal that these variants disrupt ELFN1 protein trafficking to the cell surface, resulting in loss of function. Functional modeling in mice and zebrafish demonstrates the role of Elfn1 loss in motor activity abnormalities and seizures. CONCLUSION: Our findings establish ELFN1 deficiency as the cause of a distinct, rare neurodevelopmental disorder, providing a foundation for future investigations into its pathophysiology and therapeutic strategies.

Humans↗

PubMed1992

Connectin: a homophilic cell adhesion molecule expressed on a subset of muscles and the motoneurons that innervate them in Drosophila.

Each abdominal hemisegment in the Drosophila embryo contains a stereotyped array of 30 muscles, each specifically innervated by one or a few motoneurons. We screened 11,000 enhancer trap lines, isolated several expressing beta-galactosidase in small subsets of muscle fibers prior to innervation, and identified two of these as inserts in connectin and Toll, members of the leucine-rich repeat gene family. Connectin contains a signal sequence, ten leucine-rich repeats, and a putative phosphatidylinositol membrane linkage; in S2 cells, connectin can mediate homophilic cell adhesion. Connectin is expressed on the surface of eight muscles, the motoneurons that innervate them, and several glial cells along the pathways leading to them. During synapse formation, the protein localizes to synaptic sites; afterward, it largely disappears. Thus, connectin is a novel cell adhesion molecule whose expression suggests a role in target recognition.

Amino Acid Sequence↗

PubMed1992

The rat brain postsynaptic density fraction contains a homolog of the Drosophila discs-large tumor suppressor protein.

In CNS synapses, the synaptic junctional complex with associated postsynaptic density is presumed to contain proteins responsible for adhesion between pre- and postsynaptic membranes and for postsynaptic signal transduction. We have found that a prominent, brain-specific protein (PSD-95) enriched in the postsynaptic density fraction from rat brain is highly similar to the Drosophila lethal(1)discs-large-1 (dlg) tumor suppressor protein. The dlg protein is associated with septate junctions in developing flies and contains a guanylate kinase domain that is required for normal control of cell division. The sequence similarity between dlg and PSD-95 suggests that molecular mechanisms critical for growth control in developing organisms may also regulate synapse formation, stabilization, or function in the adult brain.

Amino Acid Sequence↗

PubMed1978

The morphology of interneuronal synaptogenesis: a review.

This review has endeavored to present current findings on the morphology of synaptogenesis, summarized in Fig. 5. Though much has been discovered about the order of events and the origin of organelles, the crucial questions of why these events occur at the moment in space and time remain largely unanswered. For an understanding of the molecular basis of neuronal recognition, and of the assembly and maintenance of a functional synaptic active zone, further extensive multidisciplinary studies will be necessary.

Animals↗

PubMed1992

Long-term sensitization training in Aplysia leads to an increase in the expression of BiP, the major protein chaperon of the ER.

Long-term memory for sensitization of the gill- and siphon-withdrawal reflexes in Aplysia californica requires RNA and protein synthesis. These long-term behavioral changes are accompanied by long-term facilitation of the synaptic connections between the gill and siphon sensory and motor neurons, which are similarly dependent on transcription and translation. In addition to showing an increase in over-all protein synthesis, long-term facilitation is associated with changes in the expression of specific early, intermediate, and late proteins, and with the growth of new synaptic connections between the sensory and motor neurons of the reflex. We previously focused on early proteins and have identified four proteins as members of the immunoglobulin family of cell adhesion molecules related to NCAM and fasciclin II. We have now cloned the cDNA corresponding to one of the late proteins, and identified it as the Aplysia homolog of BiP, an ER resident protein involved in the folding and assembly of secretory and membrane proteins. Behavioral training increases the steady-state level of BiP mRNA in the sensory neurons. The increase in the synthesis of BiP protein is first detected 3 h after the onset of facilitation, when the increase in overall protein synthesis reaches its peak and the formation of new synaptic terminals becomes apparent. These findings suggest that the chaperon function of BiP might serve to fold proteins and assemble protein complexes necessary for the structural changes characteristic of long-term memory.

Amino Acid Sequence↗

PubMed2026

Pathogenic Variants in HEPACAM Alter Protein Localization and Interactome in Astrocytes of the Developing Mouse Cortex.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukodystrophy characterized by early-onset macrocephaly, white matter edema, seizures, and motor and cognitive decline. Approximately 25% of MLC patients carry HEPACAM pathogenic variants, many of which are dominant missense variants causing remitting MLC Type 2b. HEPACAM encodes hepatic and glial cell adhesion molecule (hepaCAM), also known as GlialCAM, an astrocyte-enriched transmembrane protein with important roles in astrocyte territory establishment, gap junction coupling, branching organization, synaptic function, and development of the gliovascular unit. The molecular mechanisms through which pathogenic variants in HEPACAM alter hepaCAM protein function in vivo and facilitate MLC pathogenesis during brain development remain largely unknown. Here, we used new viral tools and proximity-based proteomics to examine how three different dominant pathogenic variants alter hepaCAM subcellular localization and protein interactome in astrocytes of the developing mouse cortex. We found dramatic changes in hepaCAM distribution throughout the astrocyte, which were common to all mutants tested. We also observed significant changes in protein interactome between wild type and mutant hepaCAM, including decreased association with previously described hepaCAM-interacting proteins Connexin 43 and CLC-2. Moreover, we identified the epilepsy-associate potassium channel KCNQ2 as a novel hepaCAM interaction partner and found reduced association between KCNQ2 and pathogenic variants. Collectively, our data provide new insights into hepaCAM protein function in astrocytes during brain development, reveal altered protein dynamics of pathogenic variants, and provide a new resource to explore the molecular underpinnings of MLC pathogenesis.

Animals↗

PubMed2026

Neuropsychiatric disease mechanisms and interventions from 22q11.2 deletion syndrome experimental studies.

A high genetic predisposition for neuropsychiatric disorders, such as schizophrenia and autism spectrum disorders (ASDs), is 22q11.2 deletion syndrome (22q11DS), caused by a hemizygous microdeletion in the q-arm of human chromosome 22. The deletion most often spans a 3 Mb region, with variable breakpoints ranging from 1.5 to 3 Mb. Experimental studies on 22q11DS have revealed several aspects of the pathophysiology of neuropsychiatric disorders and also identified various interventional and rescue strategies. Herein, we review these strategies by grouping the studies into three main mechanistic categories: (i) microRNA (miR)-mediated, (ii) mitochondrial, and (iii) neural circuit deficits in polygenic deletion, and also briefly describe a few other monogenic mechanisms implicated. Haploinsufficiency of Dgcr8, a 22q11DS gene involved in miR processing, forms the center of miR-mediated mechanisms and rescuing consequent pathophysiology rely on age-dependent, brain region-specific or global replenishment of miRs or their targets. Seven genes in the 22q11.2 genomic region encode mitochondrial proteins and approaches to mitigate these gene deficiencies concentrate on the respective mitochondrial functions affected. We briefly describe other potential monogenic mechanisms for intervention including transcriptional regulation, synaptic release, catecholamine metabolism, and cell-cell adhesion, represented by Tbx1, Sept5, Comt, Arvcf, and Cldn5. We also give examples of how the multifaceted pathophysiological mechanisms and rescue strategies can have convergent effects at the molecular, synaptic, cellular and circuit levels. Based on the experimental interventions identified in the 22q11DS studies, we inform on the supportive therapies possible now and the future potential of curative interventions.

Humans↗

PubMed2026

Plasma Proteomic Signatures of Physical Activity Provide Insights into Biological Impacts and its Protective Role against Dementia.

PURPOSE: Physical activity (PA) and sedentary behavior (SB) are associated with many diseases, including Alzheimer disease and all-cause dementia. However, the specific biological mechanisms through which PA protects against disease are not entirely understood. This study aims to address this gap, with a specific focus on all-cause dementia. METHODS: We first assessed the conventional observational associations of three self-reported and three device-based PA/SB measures with circulating levels of 2911 plasma proteins measured in the UK Biobank ( nmax = 39,160) and assessed functional enrichment of identified proteins. We then used bidirectional Mendelian randomization to further evaluate the evidence for causal relationships of PA/SB with protein levels. Finally, we performed mediation analyses to identify proteins that may mediate the relationship of PA with incident all-cause dementia. RESULTS: Our findings revealed 41 proteins consistently associated with all PA measures and 1027 proteins associated with at least one PA measure. Both conventional observational and Mendelian randomization study designs converged on proteins that appear to increase as a result of PA, including integrins such as ITGAV and ITGAM, as well as MXRA8, CLEC4A, CLEC4M, LPL, and ADGRG2; and on proteins that appear to decrease as a result of PA such as LEP, INHBC, CLMP, PTGDS, ADM, OGN, and PI3; and on proteins that are more responsive to high-intensity PA, such as CA14, CA6, CA4, KIT, and ANGPT2. Functional enrichment analyses revealed processes such as cell-matrix adhesion, integrin-mediated signaling, and collagen binding. Finally, GDF15, ITGAV, ITGAM, ITGA11, HPGDS, GFAP, ADM, AHNAK, and DPP4 were among 21 unique proteins found to mediate the relationship of PA with all-cause dementia, implicating processes such as synaptic plasticity, neurogenesis, and inflammation. CONCLUSIONS: Our results provide insights into how PA affects biological processes and protects against dementia, and provide avenues for future research into the health-promoting effects of PA.

Humans↗

PubMed1992

Association of BEN glycoprotein expression with climbing fiber axonogenesis in the avian cerebellum.

In a previous study, we have identified an avian 100 kDa membrane glycoprotein that we called BEN and demonstrated that it is transiently present in the CNS and PNS on the cell somas and axons of neurons that establish the peripheral neuronal circuitry. We report here that in the developing chick cerebellar system BEN is selectively expressed on fibers whose ingrowth and synaptogenesis pattern corresponds to that described for climbing fibers. We have constructed quail-chick chimeras in which the chick mesencephalon and anterior metencephalon were replaced by their quail counterparts, thus generating a cerebellum and mesencephalon exclusively composed of quail cells whereas the main nuclei emitting afferent fibers to the cerebellar cortex were of chick origin. Then, using species-specific monoclonal antibodies we were able to show in double staining experiments that BEN protein is specifically expressed on fibers arising from the inferior olivary nucleus. The spatiotemporal pattern of BEN expression on the climbing fibers leads us to propose that this molecule is associated with the growth of these fibers and with the establishment of synapses between them and the Purkinje cell dendritic tree.

Activated-Leukocyte Cell Adhesion Molecule↗

PubMed1992

Formation of the Drosophila larval photoreceptor organ and its neuronal differentiation require continuous Krüppel gene activity.

The Drosophila segmentation gene Krüppel (Kr) is redeployed to play a critical role for the establishment of the larval visual system. Using reporter gene expression conducted by a specific Kr cis-acting element, we were able to trace back the origin of the larval photoreceptor organ, the Bolwig organ, to a single progenitor neuron and to examine Kr function in Bolwig organ development when Kr+ activity is absent from embryos due to specific mutations or reduced by neuron-specific and temporally restricted Kr antisense RNA expression. Our results show that Kr is required for neurons to differentiate into Bolwig organs, for fasciculation of the Bolwig nerve, and for this nerve to follow a specific pathway toward the synaptic targets in the larval brain. The transcription factor encoded by Kr is likely to regulate surface molecules necessary for neuronal cell adhesion and recognition in the developing larval visual system.

Animals↗

PubMed1992

Cytotactin is involved in synaptogenesis during regeneration of the frog neuromuscular system.

The expression of cytotactin, an extracellular matrix glycoprotein involved in morphogenesis and regeneration, was determined in the normal and regenerating neuromuscular system of the frog Rana temporaria. Cytotactin was expressed in adult brain and gut as two major components of Mr 190,000 and 200,000 and a minor form of higher molecular weight, but was almost undetectable in skeletal muscle extract. However, cytotactin was concentrated at the neuromuscular junctions as well as at the nodes of Ranvier. After nerve transection, cytotactin staining increased in the distal stump along the endoneurial tubes. In preparations of basal lamina sheaths of frog cutaneous pectoris muscle obtained by inducing the degeneration of both nerve and muscle fibers, cytotactin was found in dense accumulations at original synaptic sites. In order to define the role of cytotactin in axonal regeneration and muscle reinnervation, the effect of anti-cytotactin antibodies on the reinnervation of the basal lamina sheaths preparations was examined in vivo. In control preparations, regenerating nerve terminals preferentially reinnervate the original synaptic sites. In the presence of anti-cytotactin antibodies, axon regeneration occurred with normal fasciculation and branching but with altered preterminal nerve fibers pathways. Ultrastructural observations showed that synaptic basal laminae reinnervation was greatly delayed or inhibited. These results suggest that cytotactin plays a primordial role in synaptogenesis, at least during nerve regeneration and reinnervation in the adult neuromuscular system.

Animals↗

PubMed1992

Polysialic acid is associated with sodium channels and the neural cell adhesion molecule N-CAM in adult rat brain.

We have studied alpha 2,8-linked polysialic acid (polySia) and the neural cell adhesion molecule (N-CAM) in the adult rat brain by immunohistochemistry and Western blot analysis. Both molecules were widely distributed but not ubiquitous. Various brain regions showed colocalization of polySia and N-CAM. Strong immunoreactivity for polySia was seen in regions which were negative for N-CAM, such as the main and accessory olfactory bulbs. Immunohistochemical evidence for the heterogeneity of polySia expression in different brain regions was confirmed by immunoblotting. We present evidence that N-CAM is not the only polySia bearing protein in adult rat brain. Specifically, immunoprecipitation using the polySia-specific monoclonal antibody mAb 735 precipitated not only N-CAM isoforms carrying polySia, but also the sodium channel alpha subunit. Immunoblotting using sodium channel alpha subunit antibody (SP20) revealed a smear from 250 kDa upwards. PolySia removal using an endoneuraminidase specific for alpha 2,8-linked polysialic acid of 8 or more residues long, reduced this smear to a single band at 250 kDa. Thus both N-CAM and sodium channels carry homopolymers of alpha 2,8-linked polysialic acid in adult rat brain.

Animals↗

PubMed1992

GAP-43 as a plasticity protein in neuronal form and repair.

Neurons exhibit a remarkable plasticity of form, both during neural development and during the subsequent remodelling of synaptic connectivity. Here we review work on GAP-43 and G0, and focus upon the thesis that their interaction may endow neurons with such plasticity. We also present new data on the role of G proteins in neurite growth, and on the interaction of GAP-43 and actin. GAP-43 is a protein induced during periods of axonal extension and highly enriched on the inner surface of the growth cone membrane. Its membrane localization is primarily due to a short amino terminal sequence which is subject to palmitoylation. Binding to actin filaments may also assist in restricting the protein to specific cellular domains. Consistent with its role as a "plasticity protein," there is evidence that GAP-43 can directly alter cell shape and neurite extension, and several theses have been advanced for how it might do so. Two other prominent components of the growth cone membrane are the alpha and beta subunits of G0. GAP-43 regulates their guanine nucleotide exchange, which is an unusual role for an intracellular protein. We speculate that GAP-43 may adjust the "set point" of responsiveness for G0 stimulation by receptors, thereby altering the neuronal propensity to growth, without actually causing growth. To begin to address how G protein activity affects axon growth, we have developed a means to introduce guanine nucleotide analogs into sympathetic neurons. Stimulation of G proteins with GTP-gamma-S retards axon growth, whereas GDP-beta-S enhances it. This is compatible with G protein registration of inhibitory signals.

Actins↗

PubMed1992

Expression of s-laminin and laminin in the developing rat central nervous system.

The extracellular matrix component, s-laminin, is a homologue of the B1 subunit of laminin. S-laminin is concentrated in the synaptic cleft at the neuromuscular junction and contains a site that is adhesive for motor neurons, suggesting that it may influence neuromuscular development. To ascertain whether s-laminin may also play roles in the genesis of the central nervous system, we have examined its expression in the brain and spinal cord of embryonic and postnatal rats. S-laminin was not detectable in synapse-rich areas of adults. However, s-laminin was present in discrete subsets of three laminin-containing structures: (1) In the developing cerebral cortex, laminin and s-laminin were expressed in the subplate, a transient layer through which neuroblasts migrate and cortical afferents grow. Both laminin and s-laminin disappeared as embryogenesis proceeded; however, laminin was more widely distributed and present longer than s-laminin. (2) In the developing spinal cord, laminin was present throughout the pia. In contrast, s-laminin was concentrated in the pia that overlies the floor plate, a region in which extracellular cues have been postulated to guide growing axons. (3) In central capillaries, s-laminin appeared perinatally, an interval during which the blood-brain barrier matures. In contrast, laminin was present in capillary walls of both embryos and adults. To extend our immunohistochemical results, we used biochemical methods to characterize s-laminin in brain. We found that authentic s-laminin mRNA is present in the embryonic brain, but that brain-derived s-laminin differs (perhaps by a posttranslational modification) from that derived from nonneural tissues. We also used tissue culture methods to show that glia are capable of synthesizing "brain-like" s-laminin, and of assembling it into an extracellular matrix. Thus, glia may be one cellular source of s-laminin in brain. Together, these results demonstrate that s-laminin is present in the developing central nervous system, and raise the possibility that this molecule may influence developmental processes.

Animals↗