Characterization of Human Cleaved N-CAM and Association with Schizophrenia

doi:10.1006/exnr.2001.7790

Experimental Neurology

Volume 172, Issue 1, November 2001, Pages 29-46

https://doi.org/10.1006/exnr.2001.7790 Get rights and content

Abstract

The neural cell adhesion molecule (N-CAM) is a cell recognition molecule involved in cellular migration, synaptic plasticity, and CNS development. A 105- to 115-kDa isoform of N-CAM (cleaved N-CAM or cN-CAM) is increased in schizophrenia in hippocampus, prefrontal cortex, and CSF. We purified and partially characterized cN-CAM, a putative novel isoform, and confirmed that the first 9 amino acids were identical to exon 1 of N-CAM, without the signal sequence. Analysis of trypsin-digested cN-CAM fragments by matrix-assisted laser desorption ionization on a time-of-flight mass spectrometer (MALDI-TOF) yielded peptides that could be identified as being derived from the first 548 amino acid residues of the expected N-CAM amino acid sequence. Immunological identification with four specific N-CAM antisera directed toward cytoplasmic, secreted, variable alternative spliced exon, or GPI epitopes failed to indicate other known splice variants. Neuraminidase treatment of cN-CAM produced a minor alteration resulting in a faster migrating immunoreactive band, indicating partial glycosylation of cN-CAM. Membranous particles from cytosolic brain extract containing cN-CAM were obtained by ultracentrifugation; however, CSF contained few such particles. cN-CAM and synaptophysin were colocalized on these particles. Both cN-CAM and N-CAM 180 were present in synaptosomal preparations of human brain. Following incubation of synaptosomes or brain tissue without protease inhibitors, N-CAM 180 was degraded and cN-CAM was increased. A cN-CAM-like band was present in human fetal neuronal cultures, but not in fetal astrocyte cultures. Thus, cN-CAM represents a protease- and neuraminidase-susceptible fragment possibly derived by proteolytic cleavage of N-CAM 180. An enlargement in ventricular volume in a group of adult patients with schizophrenia over a 2-year interval was found to be correlated with CSF cN-CAM levels as measured at the time of the initial MRI scan (r = 0.53, P = 0.01). cN-CAM is associated with ventricular enlargement; thus, the release of N-CAM fragments may be part of the pathogenic mechanism of schizophrenia in vulnerable brain regions such as the hippocampus and prefrontal cortex. Alternatively, the increases in cN-CAM in schizophrenia may be a reflection of a more general abnormality in the regulation of proteolysis or of extracellular matrix stability.

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From genetic and etiological studies, autoimmune mechanisms underlying schizophrenia are suspected; however, the details remain unclear. In this study, we describe autoantibodies against neural cell adhesion molecule (NCAM1) in patients with schizophrenia (5.4%, cell-based assay; 6.7%, ELISA) in a Japanese cohort (n = 223). Anti-NCAM1 autoantibody disrupts both NCAM1-NCAM1 and NCAM1-glial cell line-derived neurotrophic factor (GDNF) interactions. Furthermore, the anti-NCAM1 antibody purified from patients with schizophrenia interrupts NCAM1-Fyn interaction and inhibits phosphorylation of FAK, MEK1, and ERK1 when introduced into the cerebrospinal fluid of mice and also reduces the number of spines and synapses in frontal cortex. In addition, it induces schizophrenia-related behavior in mice, including deficient pre-pulse inhibition and cognitive impairment. In conclusion, anti-NCAM1 autoantibodies in patients with schizophrenia cause schizophrenia-related behavior and changes in synapses in mice. These antibodies may be a potential therapeutic target and serve as a biomarker to distinguish a small but treatable subgroup in heterogeneous patients with schizophrenia.
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Citation Excerpt :
In addition, previous studies have reported the possible dysregulation of the NCAM system by examining cerebrospinal fluid (CSF), serum, and postmortem brain regions of schizophrenia patients. For example, early studies have found the increased NCAM in CSF (Lyons et al., 1988; Poltorak et al., 1995, 1997; Vawter et al., 2000, 2001; Vawter, Hemperly, Freed and Garver, 1998b) and postmortem brain tissues (Vawter et al., 1998a) of schizophrenia patients than healthy controls. Moreover, abnormal concentrations of CSF NCAM are associated with enlarged ventricular (Vawter et al., 2001) and clinical symptoms (Lyons et al., 1988; Vawter et al., 2000).
Neural cell adhesion molecule (NCAM) plays an important role in neurodevelopmental processes and regulates hippocampal plasticity. This study investigated the relationship between the serum NCAM concentrations and hippocampal volume and psychotic symptoms in first-episode drug naïve schizophrenia (FES) patients.
Forty-four FES patients and forty-four healthy controls (HC) were recruited in this study. Serum concentrations of NCAM were measured by ELISA. Psychiatric symptoms were assessed by the positive and negative syndrome scale (PANSS). Brain structural images were obtained using a 3T MRI Scanner and obtained T1 images were processed in order to determine hippocampal grey matter volumes.
Schizophrenia patients revealed significantly decreased serum NCAM concentrations (p = 0.017), which were positively correlated with the left (r = 0.523, p < 0.001) and right (r = 0.449, p = 0.041) hippocampal volumes, but negatively correlated with the PANSS positive symptom scores (r = −0.522 p = 0.001). However, no such correlations existed in the HC group.
This is the first time to report that decreased serum NCAM concentrations were associated with hippocampal volumes and symptom severity in FES patients. Our data indicate that the low NCAM is possible neuropathology that is associated with the decreased hippocampus in FES patients.
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Schizophrenia (SZ) and autism spectrum disorders (ASD) are characterised by marked language deficits, but it is not clear how these arise from gene mutations associated with the disorders. Our goal is to narrow the gap between SZ and ASD and, ultimately, give support to the view that they represent abnormal (but related) ontogenetic itineraries for the human faculty of language. We will focus on the distinctive oscillatory profiles of the SZ and ASD brains, in turn using these insights to refine our understanding of how the brain implements linguistic computations by exploring a novel model of linguistic feature-set composition. We will argue that brain rhythms constitute the best route to interpreting language deficits in both conditions and mapping them to neural dysfunction and risk alleles of the genes. Importantly, candidate genes for SZ and ASD are overrepresented among the gene sets believed to be important for language evolution. This translational effort may help develop an understanding of the aetiology of SZ and ASD and their high prevalence among modern populations.
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Several recent research findings indicate that schizophrenia (SCZ) may begin with an abnormal neuro-genesis from embryonic Neural Stem Cells (NSCs) and that this process may be particularly vulnerable to a number of genetic and/or environmental disturbances of early brain development. Since it is now well known that neurogenesis is not confined to the womb, but is a protracted process continuing in postnatal life well into adolescence and beyond, and since in the majority of subjects diagnosed with SCZ the first psychotic break occurs in late adolescence or early adulthood, the aim of our paper is to summarize the main findings supporting a possible link between changes in developmental postnatal neurogenesis and SCZ, with a specific focus on the critical period of adolescence and associated environmental risk factors. Establishing a significant role of adult neurogenesis in the emergence of psychosis will help us not only to better understand the pathogenesis of this neuopsychiatric disorder, but also to provide the key to potential strategies toward possible treatments and/or early corrective interventions.
Regulation of extrasynaptic signaling by polysialylated NCAM: Impact for synaptic plasticity and cognitive functions
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The activation of synaptic N-methyl-d-aspartate-receptors (NMDARs) is crucial for induction of synaptic plasticity and supports cell survival, whereas activation of extrasynaptic NMDARs inhibits long-term potentiation and triggers neurodegeneration. A soluble polysialylated form of the neural cell adhesion molecule (polySia-NCAM) suppresses signaling through peri-/extrasynaptic GluN2B-containing NMDARs. Genetic or enzymatic manipulations blocking this mechanism result in impaired synaptic plasticity and learning, which could be repaired by reintroduction of polySia, or inhibition of either GluN1/GluN2B receptors or downstream signaling through RasGRF1 and p38 MAP kinase. Ectodomain shedding of NCAM, and hence generation of soluble NCAM, is controlled by metalloproteases of a disintegrin and metalloprotease (ADAM) family. As polySia-NCAM is predominantly associated with GABAergic interneurons in the prefrontal cortex, it is noteworthy that EphrinA5/EphA3-induced ADAM10 activity promotes polySia-NCAM shedding in these neurons. Thus, in addition to the well-known regulation of synaptic NMDARs by the secreted molecule Reelin, shed polySia-NCAM may restrain activation of extrasynaptic NMDARs. These data support a concept that GABAergic interneuron-derived extracellular proteins control the balance in synaptic/extrasynaptic NMDAR-mediated signaling in principal cells. Strikingly, dysregulation of Reelin or polySia expression is linked to schizophrenia. Thus, targeting of the GABAergic interneuron-principle cell communication and restoring the balance in synaptic/extrasynaptic NMDARs represent promising strategies for treatment of psychiatric diseases.
Activity-dependent proteolytic cleavage of cell adhesion molecules regulates excitatory synaptic development and function
2017, Neuroscience Research
Citation Excerpt :
Schizophrenia is characterized by alterations to synaptic circuitry, where the spine density of cortical pyramidal neurons is markedly lower in schizophrenic patients relative to healthy controls (Garey et al., 1998; Glantz and Lewis, 2000; Glausier and Lewis, 2013). Interestingly, levels of cleaved NCAM are increased in the prefrontal cortex and hippocampus of human schizophrenia patients (Vawter et al., 2001). However, the effect or function of these cleaved NCAM fragments in the human brain is still unknown.
Activity-dependent remodeling of neuronal connections is critical to nervous system development and function. These processes rely on the ability of synapses to detect neuronal activity and translate it into the appropriate molecular signals. One way to convert neuronal activity into downstream signaling is the proteolytic cleavage of cell adhesion molecules (CAMs). Here we review studies demonstrating the mechanisms by which proteolytic processing of CAMs direct the structural and functional remodeling of excitatory glutamatergic synapses during development and plasticity. Specifically, we examine how extracellular proteolytic cleavage of CAMs switches on or off molecular signals to 1) permit, drive, or restrict synaptic maturation during development and 2) strengthen or weaken synapses during adult plasticity. We will also examine emerging studies linking improper activity-dependent proteolytic processing of CAMs to neurological disorders such as schizophrenia, brain tumors, and Alzheimer’s disease. Together these findings suggest that the regulation of activity-dependent proteolytic cleavage of CAMs is vital to proper brain development and lifelong function.

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Regular ArticleCharacterization of Human Cleaved N-CAM and Association with Schizophrenia

Abstract

Mol. Cell Neurosci.

Brain Res.

Brain Res.

Neurosci. Lett.

Neurosci. Res.

Schizophr. Res.

Anal. Biochem.

Brain Res.

Brain Res.

Neuroscience

Biol. Psychiatry

Biol. Psychiatry

Psychiatry Res.

Exp. Neurol.

Brain Res.

Int. J. Dev. Neurosci.

Exp. Gerontol.

J. Physiol Paris

Biochim. Biophys. Acta

Neuron

Biol. Psychiatry

Eur. J. Pharmacol.

Exp. Neurol.

Schizophr. Res.

Regular Article
Characterization of Human Cleaved N-CAM and Association with Schizophrenia