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Brain Advance Access originally published online on September 19, 2006
Brain 2006 129(12):3270-3276; doi:10.1093/brain/awl245
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© The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Raghavan Raju1, Goran Rakocevic1, Ziwei Chen4, Gerard Hoehn2, Cristina Semino-Mora3, Wei Shi1, Richard Olsen4 and Marinos C. Dalakas1

1 Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, Uniformed Services University of the Health Sciences Bethesda, MD 2 Critical Care Medicine Department, Clinical Center, National Institutes of Health, Uniformed Services University of the Health Sciences Bethesda, MD 3 Laboratory of Gastrointestinal and Liver Studies, Digestive Diseases Division, Uniformed Services University of the Health Sciences Bethesda, MD 4 Department of Molecular Pharmacology, University of California Los Angeles Los Angeles, CA, USA

Correspondence to: Marinos C. Dalakas, MD, Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, 10/4N252, 10 Center Drive, Bethesda, MD 20892, USA E-mail: dalakasm{at}ninds.nih.gov

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 GABAA-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 GABAA-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.

Key Words: GABA-receptor; GABARAP; proteomics; stiff-person syndrome

Abbreviations: GABARAP, GABAA-receptor-associated protein; GAD, glutamic acid decarboxylase; SPS, stiff-person sydrome

Received March 14, 2006. Revised August 7, 2006. Accepted August 10, 2006.


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[Abstract] [Full Text] [PDF]


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