Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome

Raghavan Pillai Raju, Goran Rakocevic, Ziwei Chen, Gerard Hoehn, Cristina Semino-Mora, Wei Shi, Richard Olsen, Marinos C. Dalakas

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

Stiff-person syndrome (SPS) is an autoimmune neurological disorder characterized by autoantibodies to glutamic acid decarboxylase (GAD), the enzyme responsible for the synthesis of inhibitory neurotransmitter GABA. To search for biomarkers that distinguish SPS from other neurological disorders (OND), we used surface enhanced laser desorption/ionization-time of flight (SELDI-TOF) mass spectrometry to obtain proteomic profile of sera from 25 GAD-positive SPS patients and 25 controls. A significant decrease was found in the level of a protein corresponding to GABAA-receptor-associated protein (GABARAP), which is responsible for the stability and surface expression of the GABA A-receptor. Up to 70% of the SPS sera examined, compared with 10% of the controls, immunoprecipitated GABARAP protein. Antibodies raised against GABARAP immunostained neuronal cell bodies as well as axonal and dendritic processes, as visualized by confocal microscopy. In vitro experiments demonstrated that the IgG from GABARAP antibody-positive patients, but not control IgG, significantly inhibited the surface expression of GABA A-receptor. We conclude that GABARAP is a new autoantigen in SPS. Because the patients' IgG inhibits the expression of GABAA-receptors, the circulating antibodies could impair GABAergic pathways and play a role in the clinical symptomatology of SPS patients.

Original languageEnglish (US)
Pages (from-to)3270-3276
Number of pages7
JournalBrain
Volume129
Issue number12
DOIs
StatePublished - Dec 1 2006
Externally publishedYes

Fingerprint

Stiff-Person Syndrome
GABA-A Receptors
Autoimmunity
Proteins
Glutamate Decarboxylase
Nervous System Diseases
Antibodies
Immunoglobulin G
IgG Receptors
Autoantigens
Serum
Confocal Microscopy
Autoantibodies
Proteomics
gamma-Aminobutyric Acid
Neurotransmitter Agents
Mass Spectrometry
Lasers
Biomarkers

Keywords

  • GABA-receptor
  • GABARAP
  • Proteomics
  • Stiff-person syndrome

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Raju, R. P., Rakocevic, G., Chen, Z., Hoehn, G., Semino-Mora, C., Shi, W., ... Dalakas, M. C. (2006). Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome. Brain, 129(12), 3270-3276. https://doi.org/10.1093/brain/awl245

Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome. / Raju, Raghavan Pillai; Rakocevic, Goran; Chen, Ziwei; Hoehn, Gerard; Semino-Mora, Cristina; Shi, Wei; Olsen, Richard; Dalakas, Marinos C.

In: Brain, Vol. 129, No. 12, 01.12.2006, p. 3270-3276.

Research output: Contribution to journalArticle

Raju, RP, Rakocevic, G, Chen, Z, Hoehn, G, Semino-Mora, C, Shi, W, Olsen, R & Dalakas, MC 2006, 'Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome', Brain, vol. 129, no. 12, pp. 3270-3276. https://doi.org/10.1093/brain/awl245
Raju RP, Rakocevic G, Chen Z, Hoehn G, Semino-Mora C, Shi W et al. Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome. Brain. 2006 Dec 1;129(12):3270-3276. https://doi.org/10.1093/brain/awl245
Raju, Raghavan Pillai ; Rakocevic, Goran ; Chen, Ziwei ; Hoehn, Gerard ; Semino-Mora, Cristina ; Shi, Wei ; Olsen, Richard ; Dalakas, Marinos C. / Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome. In: Brain. 2006 ; Vol. 129, No. 12. pp. 3270-3276.
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abstract = "Stiff-person syndrome (SPS) is an autoimmune neurological disorder characterized by autoantibodies to glutamic acid decarboxylase (GAD), the enzyme responsible for the synthesis of inhibitory neurotransmitter GABA. To search for biomarkers that distinguish SPS from other neurological disorders (OND), we used surface enhanced laser desorption/ionization-time of flight (SELDI-TOF) mass spectrometry to obtain proteomic profile of sera from 25 GAD-positive SPS patients and 25 controls. A significant decrease was found in the level of a protein corresponding to GABAA-receptor-associated protein (GABARAP), which is responsible for the stability and surface expression of the GABA A-receptor. Up to 70{\%} of the SPS sera examined, compared with 10{\%} of the controls, immunoprecipitated GABARAP protein. Antibodies raised against GABARAP immunostained neuronal cell bodies as well as axonal and dendritic processes, as visualized by confocal microscopy. In vitro experiments demonstrated that the IgG from GABARAP antibody-positive patients, but not control IgG, significantly inhibited the surface expression of GABA A-receptor. We conclude that GABARAP is a new autoantigen in SPS. Because the patients' IgG inhibits the expression of GABAA-receptors, the circulating antibodies could impair GABAergic pathways and play a role in the clinical symptomatology of SPS patients.",
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