Hampe, Christiane S

Honnorat, Jérome

Manto, Mario U

Rogemond, Véronique

English

PubMed

Abstract Background To investigate whether Stiff-person syndrome (SPS) and cerebellar ataxia (CA) are associated with distinct GAD65-Ab epitope specificities and neuronal effects. Methods Purified GAD65-Ab from neurological patients and monoclonal GAD65-Ab with distinct epitope specificities (b78 and b96.11) were administered in vivo to rat cerebellum. Effects of intra-cerebellar administration of GAD65-Ab were determined using neurophysiological and neurochemical methods. Results Intra-cerebellar administration of GAD65-Ab from a SPS patient (Ab SPS) impaired the NMDA-mediated turnover of glutamate, but had no effect on NMDA-mediated turnover of glycerol. By contrast, GAD65-Ab from a patient with cerebellar ataxia (Ab CA) markedly decreased the NMDA-mediated turnover of glycerol. Both GAD65-Ab increased the excitability of the spinal cord, as assessed by the F wave/M wave ratios. The administration of BFA, an inhibitor of the recycling of vesicles, followed by high-frequency stimulation of the cerebellum, severely impaired the cerebello-cortical inhibition only when Ab CA was used. Moreover, administration of transcranial direct current stimulation (tDCS) of the motor cortex revealed a strong disinhibition of the motor cortex with Ab CA. Monoclonal antibodies b78 and b96.11 showed distinct effects, with greater effects of b78 in terms of increase of glutamate concentrations, impairment of the adaptation of the motor cortex to repetitive peripheral stimulation, disinhibition of the motor cortex following tDCS, and increase of the F/M ratios. Ab SPS shared antibody characteristics with b78, both in epitope recognition and ability to inhibit enzyme activity, while Ab CA had no effect on GAD65 enzyme activity. Conclusions These results suggest that, in vivo, neurological impairments caused by GAD65-Ab could vary according to epitope specificities. These results could explain the different neurological syndromes observed in patients with GAD65-Ab.</p

Rogemond Véronique

Hampe Christiane S

Manto Mario U

Honnorat Jérome

Directory of Open Access Journals

Orphanet Journal of Rare Diseases

Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia

Abstract
          
            Background
            To investigate whether Stiff-person syndrome (SPS) and cerebellar ataxia (CA) are associated with distinct GAD65-Ab epitope specificities and neuronal effects.
          
          
            Methods
            Purified GAD65-Ab from neurological patients and monoclonal GAD65-Ab with distinct epitope specificities (b78 and b96.11) were administered in vivo to rat cerebellum. Effects of intra-cerebellar administration of GAD65-Ab were determined using neurophysiological and neurochemical methods.
          
          
            Results
            Intra-cerebellar administration of GAD65-Ab from a SPS patient (Ab SPS) impaired the NMDA-mediated turnover of glutamate, but had no effect on NMDA-mediated turnover of glycerol. By contrast, GAD65-Ab from a patient with cerebellar ataxia (Ab CA) markedly decreased the NMDA-mediated turnover of glycerol. Both GAD65-Ab increased the excitability of the spinal cord, as assessed by the F wave/M wave ratios. The administration of BFA, an inhibitor of the recycling of vesicles, followed by high-frequency stimulation of the cerebellum, severely impaired the cerebello-cortical inhibition only when Ab CA was used. Moreover, administration of transcranial direct current stimulation (tDCS) of the motor cortex revealed a strong disinhibition of the motor cortex with Ab CA. Monoclonal antibodies b78 and b96.11 showed distinct effects, with greater effects of b78 in terms of increase of glutamate concentrations, impairment of the adaptation of the motor cortex to repetitive peripheral stimulation, disinhibition of the motor cortex following tDCS, and increase of the F/M ratios. Ab SPS shared antibody characteristics with b78, both in epitope recognition and ability to inhibit enzyme activity, while Ab CA had no effect on GAD65 enzyme activity.
          
          
            Conclusions
            These results suggest that, in vivo, neurological impairments caused by GAD65-Ab could vary according to epitope specificities. These results could explain the different neurological syndromes observed in patients with GAD65-Ab.
          </jats:sec

Mario U Manto

Christiane S Hampe

Véronique Rogemond

Jérome Honnorat

Crossref

Manto, Mario

Hampe, Chris

Rogemond, Veronique

Honnorat, Jerome

DI-fusion

Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia.

Veronique Rogemond

Jerome Honnorat

Springer - Publisher Connector

International audienceBACKGROUND: To investigate whether Stiff-person syndrome (SPS) and cerebellar ataxia (CA) are associated with distinct GAD65-Ab epitope specificities and neuronal effects. METHODS: Purified GAD65-Ab from neurological patients and monoclonal GAD65-Ab with distinct epitope specificities (b78 and b96.11) were administered in vivo to rat cerebellum. Effects of intra-cerebellar administration of GAD65-Ab were determined using neurophysiological and neurochemical methods. RESULTS: Intra-cerebellar administration of GAD65-Ab from a SPS patient (Ab SPS) impaired the NMDA-mediated turnover of glutamate, but had no effect on NMDA-mediated turnover of glycerol. By contrast, GAD65-Ab from a patient with cerebellar ataxia (Ab CA) markedly decreased the NMDA-mediated turnover of glycerol. Both GAD65-Ab increased the excitability of the spinal cord, as assessed by the F wave/M wave ratios. The administration of BFA, an inhibitor of the recycling of vesicles, followed by high-frequency stimulation of the cerebellum, severely impaired the cerebello-cortical inhibition only when Ab CA was used. Moreover, administration of transcranial direct current stimulation (tDCS) of the motor cortex revealed a strong disinhibition of the motor cortex with Ab CA. Monoclonal antibodies b78 and b96.11 showed distinct effects, with greater effects of b78 in terms of increase of glutamate concentrations, impairment of the adaptation of the motor cortex to repetitive peripheral stimulation, disinhibition of the motor cortex following tDCS, and increase of the F/M ratios. Ab SPS shared antibody characteristics with b78, both in epitope recognition and ability to inhibit enzyme activity, while Ab CA had no effect on GAD65 enzyme activity. CONCLUSIONS: These results suggest that, in vivo, neurological impairments caused by GAD65-Ab could vary according to epitope specificities. These results could explain the different neurological syndromes observed in patients with GAD65-Ab

Manto, Mario, U.

Hampe, Christiane

Honnorat, Jérôme

HAL-HCL

HAL-Inserm

A role for clathrin in reassembly of the Golgi apparatus. Mol Biol Cell

AH: Blood Brain Barrier: The Role of GAD Antibodies in Psychiatry. Psychiatry (Edgmont)

AR: Cortical stimulation mapping using epidurally implanted thin-film microelectrode arrays.

Cerebellar Purkinje cells incorporate immunoglobulins and immunotoxins in vitro: implications for human neurological disease and immunotherapeutics.

Cohen LG: Modulation of rodent cortical motor excitability by somatosensory input. Exp Brain Res

Dalakas MC: Autoimmunity to GABAA-receptor-associated protein in stiffperson syndrome.

De Camilli P: Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature

E: Excellent response to steroid treatment in anti-GAD cerebellar ataxia. Lancet Neurol

Effects of anti-glutamic acid decarboxylase antibodies associated with neurological diseases. Ann Neurol

Effects of trains of high-frequency stimulation of the premotor/supplementary motor area on conditioned corticomotor responses in hemicerebellectomized rats. Exp Neurol

FA: GAD autoantibodies in IDDM, stiff-man syndrome, and autoimmune polyendocrine syndrome type I recognize different epitopes. Diabetes

Floeter MK: The stiff-person syndrome: an autoimmune disorder affecting neurotransmission of gammaaminobutyric acid. Ann Intern Med

Giometto B: Cerebellar ataxia associated with anti-glutamic acid decarboxylase autoantibodies. Cerebellum

Graus F: Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol

Guedes RC: Effects of transcranial direct current stimulation coupled with repetitive electrical stimulation on cortical spreading depression. Exp Neurol

H: Presynaptic impairment of cerebellar inhibitory synapses by an autoantibody to glutamate decarboxylase.

H: Selective loss of Purkinje cells in a patient with antiglutamic acid decarboxylase antibody-associated cerebellar ataxia.

H: Selective suppression of cerebellar GABAergic transmission by an autoantibody to glutamic acid decarboxylase. Ann Neurol

Hampe CS: Immunobiology of stiff-person syndrome. Int Rev Immunol

Hampe CS: Recombinant Fabs of human monoclonal antibodies specific to the middle epitope of GAD65 inhibit type 1 diabetes-specific GAD65Abs. Diabetes

Hemicerebellectomy blocks the enhancement of cortical motor output associated with repetitive somatosensory stimulation in the rat.

Hishida A: Stiffperson syndrome associated with cerebellar ataxia and high glutamic acid decarboxylase antibody titer. Intern Med

Human B cells secreting immunoglobulin G to glutamic acid decarboxylase- 65 from a nondiabetic patient with multiple autoantibodies and Graves’ disease: a comparison with those present in type 1 diabetes.

Inhibition of gammaaminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff-man syndrome. Annals of Neurology

Interaction between repetitive stimulation of the sciatic nerve and functional ablation of cerebellar nucleus interpositus in the rat. Cerebellum

JC: An electrophysiological investigation into the monosynaptic H-reflex in the rat. Brain Res

JY: A novel mechanism for GABA synthesis and packaging into synaptic vesicles. Neurochem Int

Klockgether T: Cerebellar ataxia with glutamic acid decarboxylase autoantibodies. Neurology

Laute MA: A possible mechanism for the beneficial effect of ethanol in essential tremor.

Lernmark Å: A novel radioligand binding assay to determine diagnostic accuracy of isoform-specific glutamic acid decarboxylase antibodies in childhood IDDM. Diabetologia

Lernmark Å: Radioimmunoassays for glutamic acid decarboxylase (GAD65) and GAD65 autoantibodies using 35So r 3H recombinant human ligands.

Lernmark A: Site-directed mutagenesis of K396R of the 65 kDa glutamic acid decarboxylase active site obliterates enzyme activity but not antibody binding. FEBS Lett

MR: Onconeuronal and control antibodies are internalized by hippocampal neurons resulting in cell death. Neurology

Ortqvist E, Hampe CS: Analysis of GAD65 Autoantibodies in Stiff-Person Syndrome Patients.

Palmitoylation controls trafficking of GAD65 from Golgi membranes to axon-specific endosomes and a Rab5a-dependent pathway to presynaptic clusters.

Plasticity and primary motor cortex. Annu Rev Neurosci

S: A palmitoylation cycle dynamically regulates partitioning of the GABAsynthesizing enzyme GAD65 between ER-Golgi and post-Golgi membranes.

Stiff person syndrome with cerebellar disease and high-titer anti-GAD antibodies. Neurology

Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition. Brain

Suppression of motor cortical excitability by electrical stimulation over the cerebellum in ataxia. Ann Neurol

Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology

T: Loss of AP-3 function affects spontaneous and evoked release at hippocampal mossy fiber synapses. Proc Natl Acad Sci USA

The cerebellum modulates rodent cortical motor output after repetitive somatosensory stimulation. Neurosurgery

The role of the synthetic enzyme GAD65 in the control of neuronal gammaaminobutyric acid release. Proc Natl Acad Sci USA

Toyka KV: Paraneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibodies to amphiphysin. Lancet

Trains of transcranial direct current stimulation antagonize motor cortex hypoexcitability induced by acute hemicerebellectomy.

Wu JY: Role of glutamate decarboxylase (GAD) isoform, GAD65, in GABA synthesis and transport into synaptic vesicles-Evidence from GAD65-knockout mice studies. Brain Res

https://ojrd.biomedcentral.com/track/pdf/10.1186/1750-1172-6-3?site=ojrd.biomedcentral.com

Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia

Abstract

Similar works

Full text

Available Versions

Directory of Open Access Journals

Crossref

DI-fusion

Springer - Publisher Connector

Springer - Publisher Connector

HAL-HCL

HAL-Inserm