TY - JOUR
T1 - Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome
AU - Raju, Raghavan
AU - Rakocevic, Goran
AU - Chen, Ziwei
AU - Hoehn, Gerard
AU - Semino-Mora, Cristina
AU - Shi, Wei
AU - Olsen, Richard
AU - Dalakas, Marinos C.
N1 - Funding Information:
This study was supported by the intramural research program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD. The authors also thank all members of the Neuromuscular Diseases Section for helpful discussion and Mr Tom Baginski from the Bioinstrumentation Center, USUHS, Bethesda, MD for technical assistance with confocal microscopy.
PY - 2006/12
Y1 - 2006/12
N2 - 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.
AB - 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.
KW - GABA-receptor
KW - GABARAP
KW - Proteomics
KW - Stiff-person syndrome
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U2 - 10.1093/brain/awl245
DO - 10.1093/brain/awl245
M3 - Article
C2 - 16984900
AN - SCOPUS:33845319790
SN - 0006-8950
VL - 129
SP - 3270
EP - 3276
JO - Brain
JF - Brain
IS - 12
ER -