N-Glycosylation of GABAA Receptor Subunits is Altered in Schizophrenia

Abstract

The molecular mechanisms of schizophrenia have been under investigation for decades; however, the exact causes of this debilitating neuropsychiatric disorder are still unknown. Previous studies have identified multiple affected neurotransmitter systems, brain regions, and cell types, each making a unique contribution to symptom presentation and pathophysiology. Numerous studies have identified gene and protein expression changes in schizophrenia, but the role of post-translational modifications, specifically N-glycosylation, has only recently become a target of investigation. N-glycosylation of molecules associated with glutamatergic neurotransmission is disrupted in schizophrenia, but it was unknown if these alterations are exclusive to the glutamatergic system or due to a more generalized deficit.In normal human cortex, we found evidence for N-glycosylation of the α1, β1, and β2 γ-aminobutyric type A receptor (GABAAR) subunits using deglycosylation protein shift assays. This was confirmed with lectin affinity assays that revealed glycan attachment on the α1, α4, and β1-3 GABAAR subunits. Examining GABAAR subunit N-glycosylation in matched pairs of schizophrenia (N=14) and comparison (N=14) of superior temporal gyrus revealed a smaller molecular mass of immature N-glycans on the α1 subunit, more immature N-glycosylation of the 49-kDa β1 subunit isoform, and altered total N-glycosylation of the β2 GABAAR subunit in schizophrenia. Measures of altered N-glycosylation of the β1 and β2 subunits were confounded by an increased apparent molecular mass of all β1 and β2 subunit isoforms in schizophrenia. Although N-glycosylation of α1, β1, and β2 were all changed in schizophrenia, the concentrations of GABAAR subunits themselves were unchanged. These findings suggest that disruptions of N-glycosylation in schizophrenia are not exclusive to glutamate and may indicate a potential disruption of a central cell signaling process in this disorder.

Lectin-Positive Spherical Deposits (SPD) Detected in the Molecular Layer of Hippocampal Dentate Gyrus of Dementia, Down’s Syndrome ,and Schizophrenia

“…In the superior temporal gyrus, altered N-glycosylation of GABAA receptor has been shown in schizophrenia [7]. In our study, it should be noticed that lectin-positive SPD in the molecular layer of dentate gyrus of hippocampal formation in patients with schizophrenia is observed also in drug naïve cases, though some experimental studies showed that a kind of therapeutic products of major tranquillizers induced neuron apoptosis in the dentate gyrus.…”

Protein Expression of Proteasome Subunits in Elderly Patients with Schizophrenia

“…If this process is disrupted, decreased 26S proteasome activity may result in the retention of misfolded proteins and/or abnormal incorporation of neurotransmitter receptor subunits into complexes that are then trafficked to the synapse. This may be a contributing factor to the abnormal N-glycosylation and subcellular localization of both glutamate and GABA receptor subunits that we have previously reported in schizophrenia (Hammond et al, 2010;Tucholski et al, 2013a, b;Mueller et al, 2014Mueller et al, , 2015. Degradation of proteins can be accomplished by several proteasome types other than the 26S, including uncapped 20S CP, the IP, and 11S γ RP-capped proteasomes.…”

Abnormal N-acetylglucosaminyltransferase expression in prefrontal cortex in schizophrenia

“…Glycosylation, ubiquitination, myristoylation, and phosphorylation are some of the PTMs that have recently been studied in schizophrenia brain (Bauer et al, 2010; Mueller et al, 2014; Pinner et al, 2014; Rubio et al, 2013; Tucholski et al, 2013a; Tucholski et al, 2013b). …”

“…Recent studies in postmortem cortex in schizophrenia have found alterations of N-linked glycosylation of the ionotropic glutamate receptor subunits GluA2 and GluK2, glutamate transporters EAAT1 and EAAT2, and γ-aminobutyric acid (GABA) A receptor subunits α1, β1, and β2 (Bauer et al, 2010; Mueller et al, 2014; Tucholski et al, 2013a; Tucholski et al, 2013b). In addition, abnormal expression of glycan structures in cerebrospinal fluid (CSF) and serum (Stanta et al, 2010), abnormal expression of sphingolipid metabolism genes (Kittler et al, 2002), and dysregulated cytoplasmic chondroitin sulfate proteoglycan expression (Macdonald et al, 2009) have all been reported in schizophrenia.…”