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

Raju, Raghavan; Rakočević, Goran; Chen, Ziwei; Hoehn, Gerard; Semino–Mora, Cristina; Shi, Wei; Olsen, Richard W.; Dalakas, Marinos C.

doi:10.1093/brain/awl245

Cited by 120 publications

(82 citation statements)

References 27 publications

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“…Applying GABARAP IgG from StiffPerson Syndrome patients decreased the surface GABA A receptors in cultured hippocampal neurons (Raju et al, 2006). Here, we provide additional evidence that GABARAP enhances the surface expression of GABA A receptors, suggesting that GABARAP facilitates the intracellular trafficking of GABA A receptors.…”

Section: Discussionmentioning

confidence: 50%

C-Terminal Modification Is Required for GABARAP-Mediated GABAA Receptor Trafficking

Chen¹,

Chang²,

Leil³

et al. 2007

Journal of Neuroscience

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We investigated the ubiquitin-like modification of GABA A receptor-associated protein (GABARAP) and its function. A fusion protein of GABARAP with v5 in the N terminus and myc in the C terminus was expressed in rat cultured hippocampal neurons and PC12 cells. Western blotting with antibodies to v5 and myc revealed that the C terminus of GABARAP was cleaved off. Cleavage was blocked by mutating the C-terminal Gly116 to Ala, suggesting that G116 is required for the processing. Unlike ubiquitin, GABARAP was not incorporated covalently into higher-molecular-weight protein complexes. Nor was GABARAP degraded by ubiquitinylation through the proteasome, although GABARAP formed noncovalent dimers. Immunofluorescent confocal microscopy demonstrated that recombinantly expressed GABARAP was diffusely localized in PC12 cells. However, prevention of C-terminal processing in the mutant GABARAP G116A resulted in redistribution to the Golgi. In neurons, punctate cytoplasmic staining of GABARAP was seen in soma and processes, whereas GABARAP G116A was limited to soma. Compared with wild-type GABARAP, the colocalization and interaction of GABARAP G116A with GABA A receptors were significantly reduced, resulting in a reduction in expression of receptors in the plasma membrane. When ␣1␤2␥2S-containing GABA A receptors were expressed in oocytes, the increased surface expression of GABA A receptors, as shown by increased GABA currents and surface-accessible GABA A receptor subunit polypeptides resulting from GABARAP coexpression, was prevented by mutation G116A. In addition, the distribution of NSF (N-ethylmaleimide-sensitive factor) was affected in GABARAP G116A -expressing neurons. These results suggest that glycine 116 is required for C-terminal processing of GABARAP and that processing is essential for the localization of GABARAP and its functions as a trafficking protein.

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Section: Discussionmentioning

confidence: 50%

C-Terminal Modification Is Required for GABARAP-Mediated GABAA Receptor Trafficking

Chen¹,

Chang²,

Leil³

et al. 2007

Journal of Neuroscience

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“…110 Receptors for glutamate and GABA can act as targets for autoantibodies, resulting in symptoms associated with those often seen in ASD. For example, antibodies against glutamate receptors have been implicated in childhood seizure disorders, 112 a common comorbidity of ASD, 111,112 whereas antibodies against GABA recep- tors are associated with motor disorders, 113 which are widely reported in ASD. 114 Although antibodies for either receptor family have not been detected in ASD, numerous unknown targets for autoantibodies exist, and it is possible that these could include subunits of the GABA or glutamate receptors.…”

Section: Neurotransmittersmentioning

confidence: 99%

Immune Dysfunction in Autism: A Pathway to Treatment

2010

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Summary: Autism is a complex and clinically heterogeneous disorder with a spectrum of symptoms. Clinicians, schools, and service agencies worldwide have reported a dramatic increase in the number of children identified with autism. Despite expanding research, the etiology and underlying biological processes of autism remain poorly understood, and the relative contribution from genetic, epigenetic, and environmental factors remains unclear. Although autism affects primarily brain function (especially affect, social functioning, and cognition), it is unknown to what extent other organs and systems are disrupted. Published findings have identified widespread changes in the immune systems of children with autism, at both systemic and cellular levels. Brain specimens from autism subjects exhibit signs of active, ongoing inflammation, as well as alterations in gene pathways associated with immune signaling and immune function. Moreover, many genetic studies have indicated a link between autism and genes that are relevant to both the nervous system and the immune system. Alterations in these pathways can affect function in both systems. Together, these reports suggest that autism may in fact be a systemic disorder with connections to abnormal immune responses. Such immune system dysfunction may represent novel targets for treatment. A better understanding of the involvement of the immune response in autism, and of how early brain development is altered, may have important therapeutic implications.

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“…Therefore, the reduced FMZ binding is best explained by reduced GABA-A receptor density on neuronal cell surfaces resulting in a reduced number of binding sites for the radiotracer. Our finding is of special interest in the light of a recent study conducted by Raju and colleagues describing autoimmunity in SPS patients against the GABA-A-receptor-associated protein (GABARAP), which is responsible for the stability and surface expression of the GABA-A receptor [14]. The authors concluded that GABARAP acts as an autoantigen in SPS patients in which antibody-mediated blocking results in a decreased availability of central postsynaptic benzodiazepine receptors.…”

Section: Discussionmentioning

confidence: 65%