Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome.
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 GABA(A)-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 GABA(A)-receptors, the circulating antibodies could impair GABAergic pathways and play a role in the clinical symptomatology of SPS patients.
Raju
Raghavan
R
Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, Uniformed Services University of the Health Sciences Bethesda, MD 20892, USA.
Rakocevic
Goran
G
Chen
Ziwei
Z
Hoehn
Gerard
G
Semino-Mora
Cristina
C
Shi
Wei
W
Olsen
Richard
R
Dalakas
Marinos C
MC
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology*; D000328:Adult; D000368:Aged; D000906:Antibodies / Q000276:immunology; D051017:Apoptosis Regulatory Proteins; D015551:Autoimmunity / Q000276:immunology*; D001369:Axons / Q000276:immunology; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology; D006624:Hippocampus / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D008297:Male; D018613:Microscopy, Confocal / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000276:immunology*; D008875:Middle Aged; D009474:Neurons / Q000276:immunology; D040901:Proteomics / Q000379:methods; D011963:Receptors, GABA-A / Q000276:immunology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D016750:Stiff-Person Syndrome / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; C116741:GABARAP protein, human; D007074:Immunoglobulin G; D008869:Microtubule-Associated Proteins; D011963:Receptors, GABA-A; D005968:Glutamate Decarboxylase