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Calpain Cleavage of Brain Glutamic Acid Decarboxylase 65 Is Pathological and Impairs GABA Neurotransmission  [PDF]
Chandana Buddhala, Marjorie Suarez, Jigar Modi, Howard Prentice, Zhiyuan Ma, Rui Tao, Jang Yen Wu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0033002
Abstract: Previously, we have shown that the GABA synthesizing enzyme, L-glutamic acid decarboxylase 65 (GAD65) is cleaved to form its truncated form (tGAD65) which is 2–3 times more active than the full length form (fGAD65). The enzyme responsible for cleavage was later identified as calpain. Calpain is known to cleave its substrates either under a transient physiological stimulus or upon a sustained pathological insult. However, the precise role of calpain cleavage of fGAD65 is poorly understood. In this communication, we examined the cleavage of fGAD65 under diverse pathological conditions including rats under ischemia/reperfusion insult as well as rat brain synaptosomes and primary neuronal cultures subjected to excessive stimulation with high concentration of KCl. We have shown that the formation of tGAD65 progressively increases with increasing stimulus concentration both in rat brain synaptosomes and primary rat embryo cultures. More importantly, direct cleavage of synaptic vesicle - associated fGAD65 by calpain was demonstrated and the resulting tGAD65 bearing the active site of the enzyme was detached from the synaptic vesicles. Vesicular GABA transport of the newly synthesized GABA was found to be reduced in calpain treated SVs. Furthermore, we also observed that the levels of tGAD65 in the focal cerebral ischemic rat brain tissue increased corresponding to the elevation of local glutamate as indicated by microdialysis. Moreover, the levels of tGAD65 was also proportional to the degree of cell death when the primary neuronal cultures were exposed to high KCl. Based on these observations, we conclude that calpain-mediated cleavage of fGAD65 is pathological, presumably due to decrease in the activity of synaptic vesicle - associated fGAD65 resulting in a decrease in the GABA synthesis - packaging coupling process leading to reduced GABA neurotransmission.
L. Yazdchi Mari,Sh. Rajieii. R. Yazdanparast
Acta Medica Iranica , 1999,
Abstract: We have Investigated the preventive effects of oral administration of isolated E.coli ghttam'tc acid decarboxylase (GAD) in animal models. Based on our results, the blood glucose levels were reduced by oral administration of GAD to rats 14 days before intraperitoneal injections of streptozocin (40 mg/kg on five consecutive days). On the other hand, oral administration of GAD to rats before streptozocin treatment significantly (P< 0.05) reduced the levels of GAD - specific antibodies and improved the in vitro proliferative responses of splenocytes to Con A- These data demonstrate tliat oral GAD administration probably generates active cellular meciianisms tliat suppress the disease and raise the possibility of using E.coli GAD as a new means for the prevention of autoimmune diabetes.
Glutamic acid decarboxylase antibody-positive paraneoplastic stiff limb syndrome associated with carcinoma of the breast
Agarwal Pankaj,Ichaporia Nasli
Neurology India , 2010,
Abstract: Stiff limb syndrome (SLS) is a rare "focal" variant of stiff person syndrome which presents with rigidity and painful spasms of a distal limb, and abnormal fixed foot or hand postures. Anti-glutamic acid decarboxylase antibodies (GAD-Ab) are variably present in most cases. Most reported cases of SLS are unassociated with cancer. We describe a patient with SLS as a paraneoplastic manifestation of breast carcinoma, in whom GAD-Ab was present. The patient responded very well to oral diazepam, baclofen and steroids.This is the third reported case of SLS as a paraneoplastic accompaniment to cancer.
Computational analysis and modeling of cleavage by the immunoproteasome and the constitutive proteasome
Carmen M Diez-Rivero, Esther M Lafuente, Pedro A Reche
BMC Bioinformatics , 2010, DOI: 10.1186/1471-2105-11-479
Abstract: We have modeled the immunoproteasome and proteasome cleavage sites upon two non-overlapping sets of peptides consisting of 553 CD8 T cell epitopes, naturally processed and restricted by human MHCI molecules, and 382 peptides eluted from human MHCI molecules, respectively, using N-grams. Cleavage models were generated considering different epitope and MHCI-eluted fragment lengths and the same number of C-terminal flanking residues. Models were evaluated in 5-fold cross-validation. Judging by the Mathew's Correlation Coefficient (MCC), optimal cleavage models for the proteasome (MCC = 0.43 ± 0.07) and the immunoproteasome (MCC = 0.36 ± 0.06) were obtained from 12-residue peptide fragments. Using an independent dataset consisting of 137 HIV1-specific CD8 T cell epitopes, the immunoproteasome and proteasome cleavage models achieved MCC values of 0.30 and 0.18, respectively, comparatively better than those achieved by related methods. Using ROC analyses, we have also shown that, combined with MHCI-peptide binding predictions, cleavage predictions by the immunoproteasome and proteasome models significantly increase the discovery rate of CD8 T cell epitopes restricted by different MHCI molecules, including A*0201, A*0301, A*2402, B*0702, B*2705.We have developed models that are specific to predict cleavage by the proteasome and the immunoproteasome. These models ought to be instrumental to identify protective CD8 T cell epitopes and are readily available for free public use at http://imed.med.ucm.es/Tools/PCPS/ webcite.CD8 cytotoxic T cells play a key role fighting intracellular pathogens, eliminating infected cells that display on their cell surface foreign peptides bound to major histocompatibility complex class I (MHCI) molecules [1-3]. CD8 T cell epitopes and, in general, peptides presented by MHCI molecules, derive from protein fragments produced in the cytosol by the proteolytic action of the proteasome [4,5]. Briefly, the proteasome generates protein fragments betwe
Glutamic acid decarboxylase antibodies are indicators of the course, but not of the onset, of diabetes in middle-aged adults: the Atherosclerosis Risk in Communities Study
Vigo, A.;Duncan, B.B.;Schmidt, M.I.;Couper, D.;Heiss, G.;Pankow, J.S.;Ballantyne, C.M.;
Brazilian Journal of Medical and Biological Research , 2007, DOI: 10.1590/S0100-879X2006005000121
Abstract: to efficiently examine the association of glutamic acid decarboxylase antibody (gada) positivity with the onset and progression of diabetes in middle-aged adults, we performed a case-cohort study representing the ~9-year experience of 10,275 atherosclerosis risk in communities study participants, initially aged 45-64 years. antibodies to glutamic acid decarboxylase (gad65) were measured by radioimmunoassay in 580 incident diabetes cases and 544 non-cases. the overall weighted prevalence of gada positivity (31 u/ml) was 7.3%. baseline risk factors, with the exception of smoking and interleukin-6 (p £ 0.02), were generally similar between gada-positive and -negative individuals. gada positivity did not predict incident diabetes in multiply adjusted (hr = 1.04; 95%ci = 0.55, 1.96) proportional hazard analyses. however, a small non-significant adjusted risk (hr = 1.29; 95%ci = 0.58, 2.88) was seen for those in the highest tertile (32.38 u/ml) of positivity. gada-positive and gada-negative non-diabetic individuals had similar risk profiles for diabetes, with central obesity and elevated inflammation markers, aside from glucose, being the main predictors. among diabetes cases at study's end, progression to insulin treatment increased monotonically as a function of baseline gada level. overall, being gada positive increased risk of progression to insulin use almost 10 times (hr = 9.9; 95%ci = 3.4, 28.5). in conclusion, in initially non-diabetic middle-aged adults, gada positivity did not increase diabetes risk, and the overall baseline profile of risk factors was similar for positive and negative individuals. among middle-aged adults, with the possible exception of those with the highest gada levels, autoimmune pathophysiology reflected by gada may become clinically relevant only after diabetes onset.
Structural characterization of the mechanism through which human glutamic acid decarboxylase auto-activates  [cached]
Christopher?G. Langendorf,Kellie?L. Tuck,Trevor?L. G. Key,Gustavo Fenalti
Bioscience Reports , 2013, DOI: 10.1042/bsr20120111
Abstract: Imbalances in GABA (γ-aminobutyric acid) homoeostasis underlie psychiatric and movement disorders. The ability of the 65 kDa isoform of GAD (glutamic acid decarboxylase), GAD65, to control synaptic GABA levels is influenced through its capacity to auto-inactivate. In contrast, the GAD67 isoform is constitutively active. Previous structural insights suggest that flexibility in the GAD65 catalytic loop drives enzyme inactivation. To test this idea, we constructed a panel of GAD65/67 chimaeras and compared the ability of these molecules to auto-inactivate. Together, our data reveal the important finding that the C-terminal domain of GAD plays a key role in controlling GAD65 auto-inactivation. In support of these findings, we determined the X-ray crystal structure of a GAD65/67 chimaera that reveals that the conformation of the catalytic loop is intimately linked to the C-terminal domain.
Anti-Yo and anti-glutamic acid decarboxylase antibodies presenting in carcinoma of the uterus with paraneoplastic cerebellar degeneration: a case report
Peter K Panegyres, Angela Graves
Journal of Medical Case Reports , 2012, DOI: 10.1186/1752-1947-6-155
Abstract: A 75-year-old Caucasian woman manifested a rapidly progressive cerebellar syndrome with nystagmus, past-pointing, dysdiadochokinesis, dysarthria, truncal ataxia and titubation. The paraneoplastic cerebellar degeneration was associated with anti-Yo and anti-glutamic acid decarboxylase antibodies. 14-3-3 protein was detected in the cerebrospinal fluid. She was treated with intravenous immunoglobulin prior to laparotomy, hysterectomy and bilateral salpingoophorectomy. Our patient has survived for three years following diagnosis and treatment.To the best of our knowledge this is the first report of an association of clear cell carcinoma of the uterus and paraneoplastic cerebellar degeneration with both anti-Yo and anti-glutamic acid decarboxylase antibodies. The findings imply that both antibodies contributed to the fulminating paraneoplastic cerebellar degeneration observed in our patient, and this was of such severity it resulted in the release of 14-3-3 protein in the cerebrospinal fluid, a marker of neuronal death.
IGF2BP2 Alternative Variants Associated with Glutamic Acid Decarboxylase Antibodies Negative Diabetes in Malaysian Subjects  [PDF]
Sameer D. Salem, Riyadh Saif-Ali, Ikram S. Ismail, Zaid Al-Hamodi, Rozaida Poh, Sekaran Muniandy
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0045573
Abstract: Background The association of Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) common variants (rs4402960 and rs1470579) with type 2 diabetes (T2D) has been performed in different populations. The aim of this study was to evaluate the association of alternative variants of IGF2BP2; rs6777038, rs16860234 and rs7651090 with glutamic acid decarboxylase antibodies (GADA) negative diabetes in Malaysian Subjects. Methods/Principal Findings IGF2BP2; rs6777038, rs16860234 and rs7651090 single nucleotide polymorphisms (SNPs) were genotyped in 1107 GADA negative diabetic patients and 620 control subjects of Asian from Malaysia. The additive genetic model adjusted for age, race, gender and BMI showed that alternative variants; rs6777038, rs16860234 and rs7651090 of IGF2BP2 associated with GADA negative diabetes (OR = 1.21; 1.36; 1.35, P = 0.03; 0.0004; 0.0002, respectively). In addition, the CCG haplotype and diplotype CCG-TCG increased the risk of diabetes (OR = 1.51, P = 0.01; OR = 2.36, P = 0.009, respectively). Conclusions/Significance IGF2BP2 alternative variants were associated with GADA negative diabetes. The IGF2BP2 haplotypes and diplotypes increased the risk of diabetes in Malaysian subject.
Cognitive decline in a patient with anti-glutamic acid decarboxylase autoimmunity; case report
Masahito Takagi, Hiroshi Yamasaki, Keiko Endo, Tetsuya Yamada, Keizo Kaneko, Yoshitomo Oka, Etsuro Mori
BMC Neurology , 2011, DOI: 10.1186/1471-2377-11-156
Abstract: We describe the clinical, neuropsychological, and neuroradiological findings of a 73-year-old female with cognitive dysfunction and type 1A diabetes. Observation and neuropsychological studies revealed linguistic problems, short-term memory disturbance, and frontal dysfunction. MRI showed no significant lesion except for confluent small T2-hyperintensity areas localized in the left basal ganglia. 18F-fluorodeoxy glucose-positron emission tomography (FDG-PET) and 123I-N-isopropyl-p-iodoamphetamine-single photon emission computed tomography (IMP-SPECT) studies showed bifrontal hypometabolism and hypoperfusion. Immunomodulating therapy with intravenous high-dose immunoglobulin resulted in no remission of the cognitive symptoms.Cognitive dysfunction may develop as an isolated neurological manifestation in association with type 1A diabetes and anti-GAD autoimmunity. A systematic study with extensive neuropsychological assessment is indicated in patients with type 1 diabetes and anti-GAD autoimmunity.Glutamic acid decarboxylase (GAD) is the biosynthesizing enzyme of the neurotransmitter γ-aminobutyric acid (GABA). Antibodies against GAD cause neurological syndromes[1], including stiff person syndrome (SPS)[2], cerebellar ataxia[3], and limbic encephalitis[4] as well as type 1 diabetes[5]. Behavioral and cognitive problems may be associated with SPS[6], limbic encephalitis[7], or cerebellar ataxia, and some of the psychiatric symptoms that have been reported in SPS[8] are considered to be related to dysfunction of the GABAergic system. However, it is not known whether dementia appears as the sole neurological manifestation associated with anti-GAD antibodies in the central nervous system. We report here a patient with GAD autoimmunity and type 1A diabetes who developed cognitive impairment without known anti-GAD-related neurological conditions.A 73-year-old, right-handed, high school-educated Japanese housewife developed polydipsia, polyuria, progressive weight loss, and i
Relationship between the prevalence of anti-glutamic acid decarboxylase autoantibodies and duration of type 1 diabetes mellitus in Brazilian patients
Rodacki, M.;Zajdenverg, L.;Albernaz, M.S.;Bencke-Gon?alves, M.R.;Milech, A.;Oliveira, J.E.P.;
Brazilian Journal of Medical and Biological Research , 2004, DOI: 10.1590/S0100-879X2004001100008
Abstract: the objective of the present study was to determine whether the duration of disease has any influence on the prevalence of glutamic acid decarboxylase autoantibodies (gada) in brazilian patients with type 1 diabetes (t1d) and variable disease duration. we evaluated 83 patients with t1d. all participants were interviewed and blood was obtained for gada measurement by a commercial radioimmunoassay (rsr limited, cardiff, uk). four groups of patients were established according to disease duration: a) 1-5 years of disease (n = 24), b) 6-10 years of disease (n = 19), c) 11-15 years of disease (n = 25), and d) >15 years of disease (n = 15). gada prevalence and its titers were determined in each group. gada was positive in 38 patients (45.8%) and its frequency did not differ between the groups. the prevalence was 11/24 (45.8%), 8/19 (42.1%), 13/25 (52%), and 6/15 (40%) in groups a, b, c, and d, respectively (p = 0.874). mean gada titer was 12.54 ± 11.33 u/ml for the sample as a whole and 11.95 ± 11.8, 12.85 ± 12.07, 10.57 ± 8.35, and 17.45 ± 16.1 u/ml for groups a, b, c, and d, respectively (p = 0.686). sex, age at diagnosis or ethnic background had no significant effect on gada (+) frequency. in conclusion, in this transversal study, duration of disease did not affect significantly the prevalence of gada or its titers in patients with t1d after one year of diagnosis. this was the first study to report this finding in the brazilian population.
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