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PubMed2002

Partial structure of glutamic acid and alanine-rich protein, a major surface glycoprotein of the insect stages of Trypanosoma congolense.

The tsetse fly transmitted salivarian trypanosome, Trypanosoma congolense of the subgenus Nanomonas, is the most significant of the trypanosomes with respect to the pathology of livestock in sub-Saharan Africa. Unlike the related trypanosome Trypanosoma brucei of the subgenus Trypanozoon, the major surface molecules of the insect stages of T. congolense are poorly characterized. Here, we describe the purification and structural characterization of the glutamic acid and alanine-rich protein, one of the major surface glycoproteins of T. congolense procyclic and epimastigote forms. The glycoprotein is a glycosylphosphatidylinositol-anchored molecule with a galactosylated glycosylphosphatidylinositol anchor containing an sn-1-stearoyl-2-l-3-HPO(4)-1-(2-O-acyl)-d-myo-inositol phospholipid moiety. The 21.6-kDa polypeptide component carries two large mannose- and galactose-containing oligosaccharides linked to threonine residues via phosphodiester linkages. Mass spectrometric analyses of tryptic digests suggest that several or all of the closely related glutamic acid and alanine-rich protein genes are expressed simultaneously in a T. congolense population growing in vitro.

Amino Acid Sequence↗
PubMed1998

Autoantigenic reactivity of diabetes sera with a hybrid glutamic acid decarboxylase GAD67-65 molecule GAD67(1-101)/GAD65(96-585).

Glutamic acid decarboxylase (GAD) is a major autoantigen in insulin-dependent diabetes mellitus (IDDM). Two GAD isoforms exist, GAD65 and GAD67, which differ mostly in the first 100 amino acids of the amino terminus. IDDM sera are predominantly reactive with GAD65 but autoepitopes have been localised only to regions of GAD65 highly homologous with GAD67. In this study we investigated the contribution of the amino terminus to the IDDM epitope on GAD65, in order to test whether this region of GAD could explain the difference in reactivity between GAD65 and GAD67. A recombinant hybrid GAD molecule consisting of amino acids 1-101 of GAD67 and 96-585 of GAD65 was constructed and a truncated GAD65 was also constructed consisting of amino acids 98-585 of GAD65. The reactivity with the hybrid GAD molecule, GAD65 and GAD67, and truncated GAD65 was examined by radioimmunoprecipitation using 50 IDDM sera with known reactivity to purified porcine brain GAD. Over 90% of the IDDM sera were reactive with the hybrid GAD molecule confirming that the amino terminus of GAD65 does not contribute to the autoepitope and that the IDDM epitope is localised to the middle and carboxyl terminal domains of GAD65. Furthermore, evidence is presented that autoantibodies to GAD65 in IDDM sera react with an epitope formed on a dimeric configuration of the molecule.

Autoantigens↗
PubMed1985

Methylmercury poisoning of the developing nervous system in the rat: decreased activity of glutamic acid decarboxylase in cerebral cortex and neostriatum.

The specific activities of glutamic acid decarboxylase (GAD) and choline acetyltransferase (ChAT) were measured in 6 regions of the central nervous system in young rats, following chronic postnatal administration of methylmercuric chloride. These rats exhibited signs of neurological impairment which included visual deficits, ataxia, spasticity and myoclonus. At the onset of neurological impairment, there was a significant reduction in GAD activity in the occipital cortex (43%), frontal cortex (37%) and caudate-putamen (42%). Preceding the onset of neurological impairment, diminished GAD activity was detected only in the occipital cortex. In the cerebellum, thalamus and spinal cord, GAD activities were normal throughout the experiment. No significant differences in ChAT activity were detected in any of the 6 regions. These results are consistent with a preferential involvement of GABAergic neurons in methylmercury-induced lesions of the cerebral cortex and neostriatum.

Age Factors↗
PubMed1996

Immunological characterization of antibodies against synthetic peptides of glutamic acid decarboxylase.

We characterized antibodies against synthetic N-terminal peptides (glutamic acid decarboxylase; GAD65N and GAD67N) and a C-terminal peptide (GAD67C) of human GAD isoforms. On Western blots, the GAD65N antibody specifically stained the 65 kDa isoform and the GAD67N antibody the 67 kDa one in various mammalian brain tissues, whereas the GAD67C antibody stained both. The immunotrapped GAD enzyme activity increased in a dose-dependent manner with increasing concentration of the N-terminal peptide antibodies, but the activity was completely inhibited by the C-terminal peptide antibody. By an enzyme-linked immunosorbent assay using rat brain GAD purified on a GAD67C antibody-affinity column, we detected GAD antibodies in 40% (24/60) of the patients with long-standing insulin-dependent diabetes mellitus (IDDM). These antipeptide antibodies are a useful tool not only for identifying the GAD isoforms, but also for purifying GAD.

Animals↗
PubMed1996

Localization of glutamic acid decarboxylase in the kidneys of nonobese diabetic mice.

Antibodies to glutamic acid decarboxylase (GAD), a pancreatic islet beta-cell antigen, are present in > 80% of newly diagnosed insulin-dependent diabetes mellitus (IDDM), and are found in nonobese diabetic (NOD) mice, a murine model of spontaneous IDDM. To determine whether GAD is a target antigen in the kidney damage of NOD mice, we studied GAD mRNAs (GAD65 and GAD67) by RT-PCR in mesangial cells, isolated glomeruli, and kidney cortex and medulla in NOD and SJL/C57BL mice. GAD mRNAs were detected in the cortex of both diabetic and nondiabetic NOD and SJL/C57BL mice and GAD antigen was present in proximal and distal tubules by immunofluorescence microscopy. Neither GAD antigen nor mRNA were present in mesangial cells or glomeruli of diabetic or nondiabetic mice. Thus, the expression of GAD in renal tubules raises the possibility that GAD antigens may play a role in diabetic tubulointerstitial disease, whereas the absence of these antigens in glomeruli suggests that GAD-triggered autoimmunity is not directly involved in the glomerular lesions.

Animals↗
PubMed1987

Elevated glutamic acid values in a malnourished patient. A case report.

Routine serum and cerebrospinal (CSF) amino acid estimations were carried out on a patient with pellagra and malnutrition. Urea levels were low and serum and CSF ammonia levels elevated. A remarkable observation was that the serum glutamic acid level rose to 44.9 times normal, which is far higher than any value reported in the medical literature. At this stage no explanation for this rise is known. Similarly no explanation can be given for the posttreatment elevation of the CSF proline levels to 13.8 times above normal.

Ammonia↗
PubMed1993

Inverse relation between humoral and cellular immunity to glutamic acid decarboxylase in subjects at risk of insulin-dependent diabetes.

Glutamic acid decarboxylase (GAD) in pancreatic beta cells is an autoantigen in insulin-dependent diabetes (IDD). We measured immunity to GAD in 31 first-degree relatives of IDD patients judged to be at risk of developing IDD themselves because of the presence of islet-cell antibodies. We found that in most of the subjects GAD autoimmunity was either predominantly humoral or predominantly cellular. High concentrations of circulating autoantibodies that precipitate native GAD activity were associated with low proliferation of peripheral-blood T cells to recombinant GAD; conversely, low concentrations of autoantibody to GAD were associated with high T-cell proliferation to GAD. Although T-cell proliferation was measured in the presence of autologous serum, GAD autoantibodies did not have a blocking effect in vitro. This dichotomy of the immune response to GAD defined heterogeneity within at-risk relatives and could have prognostic importance. We postulate that, if GAD is a pathogenetic autoantigen, sensitisation to beta-cell GAD is more likely to lead to IDD when the immune response deviates towards the expansion of autoreactive T cells rather than towards generation of autoantibodies. This idea is consistent with evidence that beta-cell destruction is mediated by T cells and that high concentrations of GAD antibodies are associated with slower progression to clinical disease.

Adolescent↗
PubMed2006

An efficient enantioselective synthesis of (2R)-hydroxymethyl glutamic acid and an approach to the (2R)-hydroxymethyl-substituted sphingofungins.

We have developed a short enantioselective synthesis of (2R)-hydroxymethyl glutamic acid (HMG) starting from Garner's aldehyde using an alkylidene carbene 1,5-CH insertion as a method to construct the quaternary stereocenter. A variety of conditions were examined for the oxidative cleavage of the key cyclopentene intermediate and we found that RuCl3/NaIO4 led directly to the desired amino bis-acid product. We were also able to show that oxidative cleavage of the cyclopentene 1,5-CH insertion product could be used to produce the amino acid-containing skeleton of the sphingofungin family of natural products.

Amino Acids↗
PubMed2000

Islet cell antibody frequency differs from that of glutamic acid decarboxylase antibodies/IA2 antibodies after diagnosis of diabetes.

The combination of glutamic acid decarboxylase (GAD) 65 antibodies (GADA) and protein tyrosine phosphatase-like protein IA2 antibodies (IA2-ab), measured by radioligand binding assays, has been suggested to replace islet cell antibodies (ICA), measured by indirect immunofluorescence, as a marker for autoimmune type I diabetes. The aim of this study was to compare the frequency of ICA and GADA and/or IA2-ab not only at, but also after the diagnosis of diabetes. ICA, GADA and IA2-ab were therefore assessed at and up to 11 y after the diagnosis of diabetes in 86 children (1-15-y-old). At diagnosis, ICA were found in 74 (86%) and GADA and/or IA2-ab in 79 (92%) of the diabetic children. Hence, there was no major difference in frequency between ICA and GADA and/or IA2-ab at diagnosis of diabetes. At follow-up, however, ICA were less frequent than GADA and/or IA2-ab; 1-3 y after diagnosis ICA were found in 12 (44%) and GADA and/or IA2-ab in 24 (89%) of 27 children (p=0.001); 4-6 y after diagnosis ICA were found in 7 (24%) and GADA and/or IA2-ab in 27 (93%) of 29 children (p < 0.0001); 7-11 y after diagnosis ICA were found in 4 (13%) and GADA and/or IA2-ab in 21 (70%) of 30 children (p < 0.0001). We conclude that the frequency of ICA does not always correspond to that of GADA and/or IA2-ab. Many years after diagnosis of diabetes, measurements of GADA and IA2-ab, but not ICA, detect autoimmunity in high frequency.

Adolescent↗
PubMed1994

Natural history of humoral immunity to glutamic acid decarboxylase in non-obese diabetic (NOD) mice.

Autoantibodies to glutamic acid decarboxylase (GAD) are present in humans before and after the onset of clinical insulin-dependent diabetes (IDD). The non-obese diabetic (NOD) mouse, a model of human IDD, develops mononuclear cell infiltration of the pancreatic islets ('insulitis') associated particularly in females with T cell-mediated destruction of the islet beta cells. In NOD mice of both sexes we detected serum antibodies to GAD (GAD Ab) that precipitate mouse brain GAD enzymatic activity. Antibodies in NOD sera also precipitate a M(r) 65,000 protein from Triton X-100 extracts of 35S-methionine-labelled NOD islets, identical in size to that precipitated by a monoclonal antibody to GAD. GAD Ab were not detected in other mouse strains. There were significant differences in the frequency, level and age at initial detection of GAD Ab between females of the NOD/Lt and NOD/WEHI lines, previously shown to have a higher and lower incidence of diabetes, respectively. Comparing NOD/Lt (n = 26) and NOD/WEHI (n = 20) females, in which diabetes occurred in 38% and 20% by 150 days, the frequency of elevated GAD Ab was 50 vs. 80%, the mean maximum GAD Ab level 21.1 vs. 30.6% and the mean age at which GAD Ab were first detected 94 vs. 45 days. No significant differences in these parameters were observed between male mice of either line. There was a significant negative correlation between the level of GAD Ab and the degree of insulitis in female mice from both lines. GAD Ab were not a prerequisite for the development of diabetes. In 7 of 10 female mice the onset of diabetes was preceded by a decrease of GAD Ab levels into the normal range. These findings indicate that, while GAD is a target of autoimmunity in the NOD mouse, GAD Ab do not necessarily correlate with the development of diabetes. Indeed, the difference between the two NOD lines and the inverse relationship with insulitis suggests that a strong humoral response to GAD may be associated with a less destructive pathology, as proposed in humans 'at-risk' for IDD.

Age Factors↗
PubMedDate not supplied

Choline acetyltransferase, glutamic acid decarboxylase and somatostatin in the kainic acid model for chronic temporal lobe epilepsy.

The aim of the study was to investigate neurochemical changes in a kainic acid (KA; 10 mg/kg, s.c.)-induced spontaneous recurrent seizure model of epilepsy, 6 months after the initial KA-induced seizures. The neuronal markers of cholinergic and gamma-aminobutyric acid (GABA)ergic systems, i.e. choline acetyltransferase (ChAT) and glutamic acid decarboxylase (GAD) activities, and a marker for neuropeptide, i.e. level of somatostatin, have been investigated. The brain regions investigated were the hippocampus, amygdala/piriform cortex, caudate nucleus, substantia nigra and the frontal, parietal, temporal and occipital cortices. Six months after KA injection, reduced ChAT activity was observed in the amygdala/piriform cortex (47% of control; p<0.001), increased ChAT activity in the hippocampus (119% of control; p<0.01) and normal ChAT activity in the other brain regions. The activity of GAD was significantly increased in all analysed cortical regions (between 146 and 171% of control), in the caudate nucleus (144% of control; p<0.01) and in the substantia nigra (126% of control; p<0.01), whereas in the amygdala/piriform cortex, the GAD activity was moderately lowered. The somatostatin level was significantly increased in all cortical regions (between 162 and 221% of control) as well as in the hippocampus (119% of control), but reduced in the amygdala/piriform cortex (45% of control; p<0.01). Six months after KA injection, the somatostatin:GAD ratio was lowered in the amygdala/piriform cortex (49% of control) and in the caudate nucleus (41% of control), whereas it was normal in the hippocampus and moderately increased in the cortical brain regions. A positive correlation was found between seizure severity and the reduction of both ChAT activities and somatostatin levels in the amygdala/piriform cortex. The results show a specific pattern of changes for cholinergic, GABAergic and somatostatinergic activities in the chronic KA model for epilepsy. The revealed data suggest a functional role for them in the new network that follows spontaneous repetitive seizures.

Animals↗
PubMed1989

A rapid purification of L-glutamic acid decarboxylase from the brain of the locust Schistocerca gregaria.

L-Glutamic acid decarboxylase (GAD; EC 4.1.1.15) was purified to apparent homogeneity from the brain of the locust Schistocerca gregaria using a combination of chromatofocusing (Mono P) and gel filtration (Superose 12) media. The homogeneity of the enzyme preparation was established by native polyacrylamide gel electrophoresis (PAGE) with silver staining. The molecular weight of the purified enzyme was estimated from native gradient gel electrophoresis and gel filtration chromatography to be 97,000 +/- 4,000 and 93,000 +/- 5,000, respectively. When analysed by sodium dodecyl sulphate-PAGE, the enzyme was found to be composed of two distinct subunits of Mr 51,000 +/- 1,000 and 44,000 +/- 1,500. Tryptic peptide maps of iodinated preparations of these two subunits showed considerable homology, suggesting that the native enzyme is a dimer of closely related subunits. The purified enzyme had a pH optimum of 7.0-7.4 in 100 mM potassium phosphate buffer and an apparent Km for glutamate of 5.0 mM. The enzyme was strongly inhibited by the carbonyl-trapping reagent aminooxyacetic acid with an I50 value of 0.2 microM.

Animals↗
PubMed1999

Determination of glutamic acid decarboxylase 65 peptides presented by the type I diabetes-associated HLA-DQ8 class II molecule identifies an immunogenic peptide motif.

Particular HLA class II allelic sequences are associated with susceptibility to type I diabetes. To understand the mechanism, knowledge of the molecular nature of the specific TCR/peptide/class II interactions involved in the disease process is required. To this end, we have introduced the diabetes-associated human class II HLA-DQ8 allele (DQA1*0301/DQB1*0302) as a transgene into mice and analyzed T cell responses restricted by this molecule to an important Ag in human diabetes, human glutamic acid decarboxylase 65. Hybridomas were used to determine the particular peptides from this Ag presented by HLA-DQ8 to T cells and to map the core minimal epitopes required for T cell stimulation. Analysis of these core epitopes reveals a motif and relevant features for peptides that are immunogenic to T cells when presented by HLA-DQ8. The major immunogenic epitopes of glutamic acid decarboxylase 65 do not contain a negatively charged residue that binds in the P9 pocket of the HLA-DQ8 molecule. PBMC from HLA-DQ8+ diabetic and nondiabetic individuals respond to these peptides, confirming that the mouse model is a useful tool to define epitopes of autoantigens that are processed by human APC and recognized by human T cells.

Animals↗
PubMed2000

4-Alkylidenyl glutamic acids, potent and selective GluR5 agonists.

Twenty-four 4-alkylidene glutamic acids were synthesised and tested as potential subtype selective GluR5 and 6 ligands. It was found that a critical size of alkylidene group gave potent and selective GluR5 receptor agonists. LY339624 had Kis of 0.0326 and >100 microM on GluR5 and 6 receptors, respectively.

Animals↗
PubMed2003

Synthesis and in vivo antitumor activity of poly(l-glutamic acid) conjugates of 20S-camptothecin.

Poly-alpha-(l-glutamic acid) (PG) conjugates of 20(S)-camptothecin (1, CPT) displayed improved aqueous solubility compared to CPT, were stable in aqueous solution at neutral pH, and were potent antitumor agents in vivo. Evaluation of PG molecular weight, CPT loading, aqueous solubility, and CPT equivalent dosing with respect to in vivo antitumor potencies of various linked conjugates led to identification of a preferred conjugate composition.

Animals↗
PubMed1997

[Effects of L-glutamic acid, gamma-aminobutyric acid and their respective antagonists on spontaneous discharge of nucleus paragigantocellularis lateralis neurons in rats].

Using multibarrel microelectrode techniques, we studied the effects of iontophoretic application of L-glutamic acid (L-Glu), gamma-aminobutyric acid (GABA) and their respective antagonists DL-2-amino-5-phosphonovaleric acid (AP5), bicuculline (BIC) on the spontaneous discharge of the caudal half of nucleus paragigantocellularis lateralis (cPGCL) neurons (including respiratory related neurons) and the influences of AP5 and BIC on the effects of L-Glu and GABA respectively in 22 anesthetized spontaneously breathing Sprague-Dawley rats. The spontaneous discharges of all the cPGCL neurons tested were inhibited by GABA(n = 53). Most of the tested neurons were excitated by L-Glu (30/36). AP5 and BIC both showed three kinds of effects on the cPGCL neuronal spontaneous discharge; excitatory, inhibitory and no-effect. The excitatory effects of L-Glu and BIC and the inhibitory effects of GABA showed a dose-response relationship. AP5 could block partially the excitatory effect of L-Glu on a large part of neurons tested (14/19). BIC blocked, partially or completely, the inhibitory effect of GABA also on a large part of the neurons tested(18/24). The results implicate that there might exist endogenous L-Glu and GABA acting as neurotransmitters in the cPGCL area and excitatory amino acids (EAA, including NMDA and non-NMDA) and GABA-receptors on cPGCL neurons. These neurotransmitters and receptors may mediate the regulatory action of cPGCL on respiration and other functional systems.

2-Amino-5-phosphonovalerate↗
PubMed2003

Normal incidence of diabetes in NOD mice tolerant to glutamic acid decarboxylase.

Experiments in nonobese diabetic (NOD) mice that lacked expression of glutamic acid decarboxylase (GAD) in beta cells have suggested that GAD represents an autoantigen essential for initiating and maintaining the diabetogenic immune response. Several attempts of inducing GAD-specific recessive tolerance to support this hypothesis have failed. Here we report on successful tolerance induction by expressing a modified form of GAD under control of the invariant chain promoter resulting in efficient epitope display. In spite of specific tolerance insulitis and diabetes occurred with normal kinetics indicating that GAD is not an essential autoantigen in the pathogenesis of diabetes.

Amino Acid Sequence↗
PubMed1989

Expression of glutamic acid decarboxylase mRNA in normal and monocularly deprived cat visual cortex.

Neurons expressing glutamic acid decarboxylase (GAD) mRNA were localized by in situ hybridization in normal and monocularly deprived cat visual cortex by using single-stranded RNA probes transcribed from cDNAs cloned in vectors with the T3 and T7 RNA polymerase promoters. In Northern blot analyses, these RNA probes identified 2 forms of GAD mRNA, one of which is approximately 200 bases longer than the other which has previously been identified. The distribution of neurons containing GAD mRNA was compared with the distribution of immunocytochemically identified GABA neurons and in both cases the highest density of labeled neurons was found in layers II, III, and upper VI. All other cellular layers contained a homogeneous, but lower density of labeled cells. Cells expressing GAD mRNA outnumbered GABA immunostained neurons by approximately 10%, but colocalization of GAD mRNA with GABA immunocytochemistry revealed that the two methodologies were detecting the same neuronal population. To determine whether decreased retinal activity affected the levels of GAD mRNA in adult cats, neurons containing GAD mRNA were counted in normal and monocularly deprived visual cortex. However, the number of cells expressing GAD mRNA did not change following monocular deprivation.

Animals↗