Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antibodies were raised against synthetic peptides corresponding to several regions of the rat brain gamma-aminobutyric acid (GABA) transporter. According to our model, this glycoprotein has 12 transmembrane alpha-helices with both amino and carboxyl termini located in the cytoplasm. The antibodies recognized the intact transporter on Western blots. Upon papain treatment, a reconstitutively active transporter can be isolated upon lectin chromatography (Kanner, B. I., Keynan, S., and Radian, R. (1989) Biochemistry 28, 3722-3728). The papainized transporter runs on sodium dodecyl sulfate-polyacrylamide gels as a broad band with an apparent molecular mass between about 58 and 68 kDa as compared to 80 kDa for the untreated transporter. The transporter fragment was recognized by all the antibodies, except for that raised against the amino terminus. Pronase cleaves the transporter to a relatively sharp 60-kDa band, which reacts with the antibodies against the internal loops but not with either the amino- or the carboxyl-terminal. This pronase-treated transporter, upon isolation by lectin chromatography, was reconstituted. It exhibits full GABA transport activity. This activity exhibits the same features as the intact system including an absolute dependence on sodium and chloride as well as electrogenicity. We conclude that the amino- and carboxyl-terminal parts of the transporter, possibly including transmembrane alpha-helices 1, 2, and 12, are not required for the transport function.
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PMID:Neither amino nor carboxyl termini are required for function of the sodium- and chloride-coupled gamma-aminobutyric acid transporter from rat brain. 173 54

The sodium- and chloride-coupled gamma-aminobutyric transporter, an 80-kDa glycoprotein, has been subjected to deglycosylation and limited proteolysis. The treatment of the 80-kDa band with endoglycosidase F results in its disappearance and reveals the presence of a polypeptide with an apparent molecular mass of about 60 kDa, which is devoid of 125I-labeled wheat germ agglutinin binding activity but is nevertheless recognized by the antibodies against the 80-kDa band. Upon limited proteolysis with papain or Pronase, the 80-kDa band was degraded to one with an apparent molecular mass of about 60 kDa. This polypeptide still contains the 125I-labeled wheat germ agglutinin binding activity but is not recognized by the antibody. The effect of proteolysis on function was examined. The transporter was purified by use of all steps except that for the lectin chromatography [Radian, R., Bendahan, A., & Kanner, B.I. (1986) J. Biol. Chem. 261, 15437-15441]. After papain treatment and lectin chromatography, gamma-aminobutyric transport activity was eluted with N-acetylglucosamine. The characteristics of transport were the same as those of the pure transporter, but the preparation contained instead of the 80-kDa polypeptide two fragments of about 66 and 60 kDa. The ability of the anti-80-kDa antibody to recognize these fragments was relatively low. The observations indicate that the transporter contains exposed domains which are not important for function.
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PMID:Structural and functional studies on the sodium- and chloride-coupled gamma-aminobutyric acid transporter: deglycosylation and limited proteolysis. 250 69

Autism is a severe neurodevelopmental disorder with potential genetic and environmental causes. Cerebellar pathology including Purkinje cell atrophy has been demonstrated previously. We hypothesized that cell migration and apoptotic mechanisms may account for observed Purkinje cell abnormalities. Reelin is an important secretory glycoprotein responsible for normal layering of the brain. Bcl-2 is a regulatory protein responsible for control of programmed cell death in the brain. Autistic and normal control cerebellar corteces matched for age, sex, and post-mortem interval (PMI) were prepared for SDS-gel electrophoresis and Western blotting using specific anti-Reelin and anti-Bcl-2 antibodies. Quantification of Reelin bands showed 43%, 44%, and 44% reductions in autistic cerebellum (mean optical density +/- SD per 30 microg protein 4.05 +/- 4.0, 1.98 +/- 2.0, 13.88 +/- 11.9 for 410 kDa, 330 kDa, and 180 kDa bands, respectively; N = 5) compared with controls (mean optical density +/- SD per 30 microg protein, 7.1 +/- 1.6, 3.5 +/- 1.0, 24.7 +/- 5.0; N = 8, p < 0.0402 for 180 kDa band). Quantification of Bcl-2 levels showed a 34% to 51% reduction in autistic cerebellum (M +/- SD per 75 microg protein 0.29 +/- 0.08; N = 5) compared with controls (M +/- SD per 75 microg protein 0.59 +/- 0.31; N = 8, p < 0.0451). Measurement of beta-actin (M +/- SD for controls 7.3 +/- 2.9; for autistics 6.77 +/- 0.66) in the same homogenates did not differ significantly between groups. These results demonstrate for the first time that dysregulation of Reelin and Bcl-2 may be responsible for some of the brain structural and behavioral abnormalities observed in autism.
J Autism Dev Disord 2001 Dec
PMID:Dysregulation of Reelin and Bcl-2 proteins in autistic cerebellum. 1181 62

Reelin is a large extracellular glycoprotein that is defective in reeler mutant mice and plays a well-established role during brain development in human as well as rodents. In the adult brain, Reelin is expressed in a subset of GABAergic interneurons. Its role in disease states is not clearly defined, although it is implicated in autism and psychoses such as schizophrenia. In this report, we show that Reelin immunoreactive proteins can be detected in the human cerebrospinal fluid (CSF) with monoclonal antibodies directed against the N- and C-terminal regions of the protein. In CSF, Reelin is present as different products due to processing at two main sites; preservation at -20 degrees C increases processing further. CSF Reelin originates from the brain tissue and not from plasma. The protein was detected in comparable concentrations in children and adults, and the signal varied largely from subject to subject with no obvious correlation with age or neurological disease state.
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PMID:Characterization of the various forms of the Reelin protein in the cerebrospinal fluid of normal subjects and in neurological diseases. 1500 2

Reelin glycoprotein is a secretory serine protease with dual roles in mammalian brain: embryologically, it guides neurons and radial glial cells to their corrected positions in the developing brain; in adult brain, Reelin is involved in a signaling pathway which underlies neurotransmission, memory formation and synaptic plasticity. Disruption of Reelin signaling pathway by mutations and selective hypermethylation of the Reln gene promoter or following various pre- or postnatal insults may lead to cognitive deficits present in neuropsychiatric disorders like autism or schizophrenia.
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PMID:Reelin glycoprotein: structure, biology and roles in health and disease. 1558 3

Reelin is an extracellular matrix glycoprotein that plays an important role in guiding neuronal migration, lamination and connection during embryonic brain development. Several reports suggest that reduced reelin expression is associated with human mental illnesses such as schizophrenia, mood disorders and autism. Human reelin cDNA has been cloned and contains a polymorphic GGC repeat at the 5' untranslated region. In view of the possible regulation of reelin gene expression by this GGC polymorphism, we investigated the association of the polymorphic GGC repeat with schizophrenia in a Chinese Han population from Taiwan. We found no differences of allelic and genotypic distributions of the polymorphic GGC triplets between 162 schizophrenic patients and 176 controls in this study. Our findings do not support the involvement of the polymorphic GGC triplets of the reelin gene in the pathogenesis of schizophrenia in the population studied.
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PMID:Absence of association of a polymorphic GGC repeat at the 5' untranslated region of the reelin gene with schizophrenia. 1655 65

Autistic disorder is a neurodevelopmental disorder where genetic factors play an important role. We previously described an association between a subgroup of French autistic patients and an allele of a non-synonymous single nucleotide polymorphism (nsSNP: OMGP62 G>A or rs11080149) in the gene coding for the oligodendrocyte and myelin glycoprotein (OMG), located at 7Mb from the marker D17S250, linked to autism in two independent genome scan studies. We report a study on 431 families with 1 affected child from different origins: French Canada (n=262), Italy (n=123) and United States (n=46). We analyzed the transmission of the rs11080149 alleles from parents to their affected children. There was a preferential transmission of the G allele from parents to affected children (p=0.0017) in the overall sample. Paternal and maternal transmission rates were both skewed. Taking into account our previous results obtained in a French group of patients, where we observed an association with allele A, a direct role of this polymorphism is improbable in autism. The associations observed in Japanese and French patients, the linkage studies and the present work speak in favor of the existence of a susceptibility gene for autism in the NF1 locus.
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PMID:Transmission disequilibrium study of an oligodendrocyte and myelin glycoprotein gene allele in 431 families with an autistic proband. 1789 45

Recent research and clinical data have begun to demonstrate the huge potential therapeutic importance of ligands that modulate the activity of the secretin-like, Class II, G protein-coupled receptors (GPCRs). Ligands that can modulate the activity of these Class II GPCRs may have important clinical roles in the treatment of a wide variety of conditions such as osteoporosis, diabetes, amyotrophic lateral sclerosis and autism spectrum disorders. While these receptors present important new therapeutic targets, the large glycoprotein nature of their cognate ligands poses many problems with respect to therapeutic peptidergic drug design. These native peptides often exhibit poor bioavailability, metabolic instability, poor receptor selectivity and resultant low potencies in vivo. Recently, increased attention has been paid to the structural modification of these peptides to enhance their therapeutic efficacy. Successful modification strategies have included d-amino acid substitutions, selective truncation, and fatty acid acylation of the peptide. Through these and other processes, these novel peptide ligand analogs can demonstrate enhanced receptor subtype selectivity, directed signal transduction pathway activation, resistance to proteolytic degradation, and improved systemic bioavailability. In the future, it is likely, through additional modification strategies such as addition of circulation-stabilizing transferrin moieties, that the therapeutic pharmacopeia of drugs targeted towards Class II secretin-like receptors may rival that of the Class I rhodopsin-like receptors that currently provide the majority of clinically used GPCR-based therapeutics. Currently, Class II-based drugs include synthesized analogs of vasoactive intestinal peptide for type 2 diabetes or parathyroid hormone for osteoporosis.
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PMID:Chemical modification of class II G protein-coupled receptor ligands: frontiers in the development of peptide analogs as neuroendocrine pharmacological therapies. 1968 75

Epidemiological studies implicate prenatal infection as a risk factor for the development of schizophrenia and autism. Subjects with schizophrenia and autism are reported to exhibit reduced levels of glutamic acid decarboxylase 67 (GAD67), a marker for GABA neurons, in various brain regions. Reduced levels of reelin, a secretory glycoprotein present in a subpopulation of GABA neurons, have also been found in these disorders. To test if prenatal infection can cause abnormalities in GAD67 and reelin in the brains of offspring, this study used a rat model of prenatal exposure to the bacterial endotoxin, lipopolysaccharide (LPS), and assessed numbers of GAD67-immunoreactive (GAD67+) and reelin-immunoreactive (reelin+) neurons in the hippocampus of offspring. In offspring at postnatal day 14 (PD14), GAD67+ cell counts were reduced in the dentate gyrus of the prenatal LPS group compared to prenatal saline controls, while at PD28, GAD67+ cells counts were reduced in the prenatal LPS group in both the dentate gyrus and the CA1. There was a decrease in the number of reelin+ cells in the prenatal LPS offspring compared to controls in the dentate gyrus at PD14. However using Western blotting, no significant effects of prenatal LPS on levels of GAD67 or reelin protein were observed in various brain regions at PD14. These findings support the idea that prenatal infection can cause reductions in postnatal expression of GAD67 and reelin, and in this way, possibly contribute to the pathophysiology of schizophrenia or autism.
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PMID:Prenatal exposure to bacterial endotoxin reduces the number of GAD67- and reelin-immunoreactive neurons in the hippocampus of rat offspring. 2188 16

Reelin is a glycoprotein that serves important roles both during development (regulation of neuronal migration and brain lamination) and in adulthood (maintenance of synaptic function). A number of neuropsychiatric disorders including autism, schizophrenia, bipolar disorder, major depression, Alzheimer's disease and lissencephaly share a common feature of abnormal Reelin expression in the brain. Altered Reelin expression has been hypothesized to impair neuronal connectivity and synaptic plasticity, leading ultimately to the cognitive deficits present in these disorders. The mechanisms for abnormal Reelin expression in some of these disorders are currently unknown although possible explanations include early developmental insults, mutations, hypermethylation of the promoter for the Reelin gene (RELN), miRNA silencing of Reelin mRNA, FMRP underexpression and Reelin processing abnormalities. Increasing Reelin expression through pharmacological therapies may help ameliorate symptoms resulting from Reelin deficits. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'.
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PMID:The involvement of Reelin in neurodevelopmental disorders. 2298 49


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