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

In the present study we describe a sensitive ELISA for determination of glial fibrillary acidic protein (GFAP). To validate the method combined determinations of GFAP and S-100 protein were performed in cerebrospinal fluid (CSF) of normal children and children with autism. The GFAP ELISA is of sandwich type and uses the biotin-avidin system. Sensitivity was 16 pg/ml. Between-day precision was 0.079 (coeff. of variance). S-100 protein concentrations were measured using a commercially available ELISA kit. Normal CSF from children and young adults were analysed. The CSF levels of GFAP in normal children were low (16-163 pg/ml). Both GFAP and S-100 protein concentrations correlated with age (P < 0.01 and P < 0.05, respectively), but the GFAP increment was more pronounced, probably reflecting the age-dependent expansion of the fibrillary astrocytes in the central nervous system (CNS). GFAP levels in children with infantile autism were higher than those in normal children of the same age range. S-100 protein concentrations were similar in both groups. High levels of GFAP in combination with normal S-100 protein concentrations in CSF indicates reactive astrogliosis in the CNS. In conclusion, the sensitive ELISA described makes it possible to measure low levels of GFAP present in the CSF of children. Combined assays of GFAP and S-100 protein can be used to discriminate between acute and chronic brain disorders in children.
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PMID:A sensitive ELISA for glial fibrillary acidic protein: application in CSF of children. 147 47

The cerebrospinal fluid (CSF) of 47 children and adolescents with autism was analyzed for the contents of two astroglial proteins, the glial fibrillary acidic protein (GFA) and S 100. The results were contrasted with those obtained in similarly aged cases with other neuropsychiatric disorders (n = 25) and in normal children (n = 10). S-100 did not discriminate the groups from each other. However, GFA in autism and autistic-like conditions was at a level almost three times that in the normal group. The results could implicate gliosis and unspecific brain damage in autism. An alternative model would be increased synapse turnover regardless of underlying cause.
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PMID:Glial fibrillary acidic protein in the cerebrospinal fluid of children with autism and other neuropsychiatric disorders. 835 69

Autoimmunity may be a pathogenic factor in autism, a behavioral disorder of early childhood onset. Circulating autoantibodies are produced in organ-specific autoimmunity; therefore, we investigated them in the plasma of autistic subjects, mentally retarded (MR) subjects, and healthy controls. Autoantibodies (IgG isotype) to neuron-axon filament protein (anti-NAFP) and glial fibrillary acidic protein (anti-GFAP) were analyzed by the Western immunoblotting technique. We found a significant increase in incidence of anti-NAFP (P = .004) and anti-GFAP (P = .002) in autistic subjects, but not in MR subjects. Clinically, these autoantibodies may be related to autoimmune pathology in autism.
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PMID:Circulating autoantibodies to neuronal and glial filament proteins in autism. 930 86

Cortical tubers are developmental brain malformations in the tuberous sclerosis complex (TSC) that cause epilepsy and autism in TSC patients whose pathogenesis is uncertain. Tsc2 null murine neuroepithelial progenitor (NEP) cells display persistent growth when growth factors are withdrawn, express GFAP at high levels, and have reduced expression of a set of early neuronal lineage markers. Tsc2 null NEP cells exhibit aberrant differentiation into giant cells that express both beta III-tubulin and GFAP and that are morphologically similar to giant cells in human tubers. Tsc2 null giant cells and tuber giant cells have similar transcriptional profiles. Tsc2 null NEP cells express high levels of phosphorylated S6kinase, S6, Stat3, and 4E-BP-1, which is reversed by treatment with rapamycin, an inhibitor of mTOR. We conclude that giant cells in human tubers likely result from a complete loss of TSC2 expression and activation of an mTOR pathway during cortical development.
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PMID:Tsc2 null murine neuroepithelial cells are a model for human tuber giant cells, and show activation of an mTOR pathway. 1250 90

Individuals with tuberous sclerosis complex (TSC) exhibit a variety of neurologic abnormalities, including mental retardation, epilepsy, and autism. Examination of human TSC brains demonstrate dysplastic astrocytes and neurons, areas of abnormal neuronal migration (tubers), and hamartomatous growths, termed subependymal nodules, which can progress to subependymal giant cell astrocytomas (SEGA). Previous studies have suggested that these neuropathologic features may result from abnormal neuroglial cell differentiation. In an effort to provide support for this hypothesis and to identify specific markers of aberrant neuroglial cell differentiation in TSC, we employed gene expression profiling on Tsc1 conditional knockout (Tsc1(GFAP)CKO) mouse astrocytes. We identified several transcripts implicated in central nervous system development that are differentially expressed in Tsc1(-/-) astrocytes compared to wild-type astrocytes. We validated the differential expression of select transcripts on the protein level both in primary cultures of Tsc1(-/-) astrocytes and in Tsc1(GFAP)CKO mouse brains. Moreover, we show that these markers are also differentially expressed within cortical tubers, but not in adjacent normal tissue from TSC patient brains. This study provides supportive evidence for a developmental defect in neuroglial cell differentiation relevant to the genesis of TSC nervous system pathology and underscores the utility of mouse modeling for understanding the molecular pathogenesis of human disease.
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PMID:Expression profiling in tuberous sclerosis complex (TSC) knockout mouse astrocytes to characterize human TSC brain pathology. 1499 11

Cytokines have been implicated in the etiology or pathology of various psychiatric diseases of developmental origin such as autism and schizophrenia. Leukemia inhibitory factor (LIF) is induced by a variety of brain insults and known to have many influences on mature and immature nervous system. Here, we assessed the neurobehavioral and pathological consequences of peripheral administration of LIF in newborn rats. Subcutaneous LIF injection induced STAT3 phosphorylation in many brain regions and increased glial fibrillary acidic protein (GFAP) immunoreactivity in the neocortex, suggesting that LIF had direct effects in the central nervous system. The LIF-treated rats displayed decreased motor activity during juvenile stages, and developed abnormal prepulse inhibition in the acoustic startle test during and after adolescence. They displayed normal learning ability in active avoidance test, however. Brain neuronal structures and startle responses were grossly normal, except for the cortical astrogliosis during neonatal LIF administration. These results indicate that LIF induction in the periphery of the infant has a significant, but discrete impact on neurobehavioral development.
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PMID:Neonatal impact of leukemia inhibitory factor on neurobehavioral development in rats. 1515 80

Autism is a debilitating neurodevelopmental disorder of early childhood with both genetic and environmental origins. Immune system dysregulation has been hypothesized to be involved in this disorder. We quantified levels of glial fibrillary acidic protein (GFAP) and ss-actin in three areas of the brain, namely, area 9, area 40 and cerebellum, in age matched autistic and control postmortem specimen using SDS-PAGE and western blotting techniques. Significant elevations in levels of GFAP were observed in all three brain areas in autism. This report confirms a recent report showing microglial and astroglial activation in autism. Increased GFAP levels in autistic brains signify gliosis, reactive injury, and perturbed neuronal migration processes.
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PMID:Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects. 1614 53

The immunopathogenesis of autism is presented schematically in Fig. 1. Two main immune dysfunctions in autism are immune regulation involving pro-inflammatory cytokines and autoimmunity. Mercury and an infectious agent like the measles virus are currently two main candidate environmental triggers for immune dysfunction in autism. Genetically immune dysfunction in autism involves the MHC region, as this is an immunologic gene cluster whose gene products are Class I, II, and III molecules. Class I and II molecules are associated with antigen presentation. The antigen in virus infection initiated by the virus particle itself while the cytokine production and inflammatory mediators are due to the response to the putative antigen in question. The cell-mediated immunity is impaired as evidenced by low numbers of CD4 cells and a concomitant T-cell polarity with an imbalance of Th1/Th2 subsets toward Th2. Impaired humoral immunity on the other hand is evidenced by decreased IgA causing poor gut protection. Studies showing elevated brain specific antibodies in autism support an autoimmune mechanism. Viruses may initiate the process but the subsequent activation of cytokines is the damaging factor associated with autism. Virus specific antibodies associated with measles virus have been demonstrated in autistic subjects. Environmental exposure to mercury is believed to harm human health possibly through modulation of immune homeostasis. A mercury link with the immune system has been postulated due to the involvement of postnatal exposure to thimerosal, a preservative added in the MMR vaccines. The occupational hazard exposure to mercury causes edema in astrocytes and, at the molecular level, the CD95/Fas apoptotic signaling pathway is disrupted by Hg2+. Inflammatory mediators in autism usually involve activation of astrocytes and microglial cells. Proinflammatory chemokines (MCP-1 and TARC), and an anti-inflammatory and modulatory cytokine, TGF-beta1, are consistently elevated in autistic brains. In measles virus infection, it has been postulated that there is immune suppression by inhibiting T-cell proliferation and maturation and downregulation MHC class II expression. Cytokine alteration of TNF-alpha is increased in autistic populations. Toll-like-receptors are also involved in autistic development. High NO levels are associated with autism. Maternal antibodies may trigger autism as a mechanism of autoimmunity. MMR vaccination may increase risk for autism via an autoimmune mechanism in autism. MMR antibodies are significantly higher in autistic children as compared to normal children, supporting a role of MMR in autism. Autoantibodies (IgG isotype) to neuron-axon filament protein (NAFP) and glial fibrillary acidic protein (GFAP) are significantly increased in autistic patients (Singh et al., 1997). Increase in Th2 may explain the increased autoimmunity, such as the findings of antibodies to MBP and neuronal axonal filaments in the brain. There is further evidence that there are other participants in the autoimmune phenomenon. (Kozlovskaia et al., 2000). The possibility of its involvement in autism cannot be ruled out. Further investigations at immunological, cellular, molecular, and genetic levels will allow researchers to continue to unravel the immunopathogenic mechanisms' associated with autistic processes in the developing brain. This may open up new avenues for prevention and/or cure of this devastating neurodevelopmental disorder.
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PMID:Immunological findings in autism. 1651 56

Clinical observations suggest that certain gut and dietary factors may transiently worsen symptoms in autism spectrum disorders (ASD), epilepsy and some inheritable metabolic disorders. Propionic acid (PPA) is a short chain fatty acid and an important intermediate of cellular metabolism. PPA is also a by-product of a subpopulation of human gut enterobacteria and is a common food preservative. We examined the behavioural, electrophysiological, neuropathological, and biochemical effects of treatment with PPA and related compounds in adult rats. Intraventricular infusions of PPA produced reversible repetitive dystonic behaviours, hyperactivity, turning behaviour, retropulsion, caudate spiking, and the progressive development of limbic kindled seizures, suggesting that this compound has central effects. Biochemical analyses of brain homogenates from PPA treated rats showed an increase in oxidative stress markers (e.g., lipid peroxidation and protein carbonylation) and glutathione S-transferase activity coupled with a decrease in glutathione and glutathione peroxidase activity. Neurohistological examinations of hippocampus and adjacent white matter (external capsule) of PPA treated rats revealed increased reactive astrogliosis (GFAP immunoreactivity) and activated microglia (CD68 immunoreactivity) suggestive of a neuroinflammatory process. This was coupled with a lack of cytotoxicity (cell counts, cleaved caspase 3' immunoreactivity), and an increase in phosphorylated CREB immunoreactivity. We propose that some types of autism may be partial forms of genetically inherited or acquired disorders involving altered PPA metabolism. Thus, intraventricular administration of PPA in rats may provide a means to model some aspects of human ASD in rats.
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PMID:Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. 1695 May 24

Controversy exists over the role of autoantibodies to central nervous system antigens in autism and Tourette Syndrome. We investigated plasma autoantibody titers to glial fibrillary acidic protein (GFAP) in children with classic onset (33) and regressive onset (26) autism, controls (25, healthy age- and gender-matched) and individuals with Tourette Syndrome (24) by enzyme-linked immunosorbent assays. We found a significant difference in autoantibody titers to GFAP, not accounted for by age, between the Tourette (significantly lower) and regressive autism groups. However, no differences were found between: classic/regressive; classic/controls; classic/Tourette; regressive/controls; or controls/Tourette. Autoantibody responses against GFAP are unlikely to play a pathogenic role in autism or Tourette Syndrome.
J Autism Dev Disord 2008 Feb
PMID:How relevant are GFAP autoantibodies in autism and Tourette Syndrome? 1757 59


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