Brain Advance Access published online on September 19, 2006
Brain, doi:10.1093/brain/awl245
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1 Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
* To whom correspondence should be addressed. 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.
Received March 14, 2006
Revised August 7, 2006
Accepted August 10, 2006
Article
Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome
Raghavan Raju 1, Goran Rakocevic 1, Ziwei Chen 2, Gerard Hoehn 3, Cristina Semino-Mora 4, Wei Shi 1, Richard Olsen 2, and Marinos C. Dalakas 1 *
2 Department of Molecular Pharmacology, University of California Los Angeles, Los Angeles, CA, USA
3 Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA
4 Laboratory of Gastrointestinal and Liver Studies, Digestive Diseases Division, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
Marinos C. Dalakas, E-mail: dalakasm{at}ninds.nih.gov
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