N-Glycosylation of GABAA Receptor Subunits is Altered in Schizophrenia
N-Glycosylation of GABAA Receptor Subunits is Altered in Schizophrenia
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DOI：
10.1038/npp.2013.190
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发表时间：
2014-02-01
影响因子：
7.6
通讯作者：
Meador-Woodruff, James H.
中科院分区：
文献类型：
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作者：
Mueller, Toni Marie;Haroutunian, Vahram;Meador-Woodruff, James H.
精神分裂症的分子机制已经研究了几十年;然而，这种使人衰弱的神经精神障碍的确切原因仍然未知。以前的研究已经确定了多个受影响的神经递质系统，大脑区域和细胞类型，每个都对症状表现和病理生理学做出了独特的贡献。许多研究已经确定了精神分裂症的基因和蛋白质表达的变化，但翻译后修饰的作用，特别是N-糖基化，最近才成为调查的目标。精神分裂症中与谷氨酸能神经传递相关的分子的N-糖基化被破坏，但尚不清楚这些改变是谷氨酸能系统独有的还是由于更广泛的缺陷。在正常人皮质，我们发现的证据N-糖基化的α 1，α 1和β 2 γ-氨基丁酸A型受体（GABAAR）亚基使用去糖基化蛋白质位移测定。这用凝集素亲和试验证实，该试验显示聚糖附着在α 1、α 4和β 1-3 GABAAR亚基上。检查精神分裂症配对（N 14）和上级颞回比较（N 14）中GABAAR亚基N-糖基化，发现α 1亚基上的不成熟N-聚糖分子量较小，49 kDa β 1亚基同种型的不成熟N-糖基化更多，精神分裂症中β 2 GABAAR亚基的总N-糖基化改变。β 1和β 2亚基的N-糖基化改变的测量结果被精神分裂症中所有β 1和β 2亚基亚型的表观分子量增加所混淆。虽然α 1、β 1和β 2的N-糖基化在精神分裂症中都发生了变化，但GABAAR亚基本身的浓度没有变化。这些研究结果表明，精神分裂症中的N-糖基化的破坏并不局限于谷氨酸，并且可能表明这种疾病中的中央细胞信号传导过程的潜在破坏。
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 alpha 1, alpha 1, and beta 2 gamma-aminobutyric type A receptor (GABAAR) subunits using deglycosylation protein shift assays. This was confirmed with lectin affinity assays that revealed glycan attachment on the alpha 1, alpha 4, and beta 1-3 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 alpha 1 subunit, more immature N-glycosylation of the 49-kDa beta 1 subunit isoform, and altered total N-glycosylation of the beta 2 GABAAR subunit in schizophrenia. Measures of altered N-glycosylation of the beta 1 and beta 2 subunits were confounded by an increased apparent molecular mass of all beta 1 and beta 2 subunit isoforms in schizophrenia. Although N-glycosylation of alpha 1, beta 1, and beta 2 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.