Clinical Brain Disorders Branch, National Institutes of Mental Health, National Institute of Health, Bethesda, MD 20892-1385, USA.
Transl Psychiatry. 2011 Aug 16;1(8):e30. doi: 10.1038/tp.2011.31.
Numerous genetic linkage and association reports have implicated the Disrupted-in-Schizophrenia (DISC1) gene in psychiatric illness. The Scottish family translocation, predicted to encode a C-terminus-truncated protein, suggests involvement of short isoforms in the pathophysiology of mental disorders. We recently reported complex alternative splicing patterns for the DISC1 gene and found that short isoforms are overexpressed in the brains of patients with schizophrenia and in carriers of risk-associated alleles. Investigation into the protein-protein interactions of alternative DISC1 isoforms may provide information about the functional consequences of overexpression of truncated forms in mental illness. Human embryonic kidney (HEK293) cells were transiently co-transfected with human epitope-tagged DISC1 variants and epitope-tagged NDEL1, FEZ1, GSK3β and PDE4B constructs. Co-immunoprecipitation assays demonstrated that all truncated DISC1 variants formed complexes with full-length DISC1. Short DISC1 splice variants LΔ78, LΔ3 and Esv1 showed reduced or no binding to NDEL1 and PDE4B proteins, but fully interacted with FEZ1 and GSK3β. The temporal expression pattern of GSK3β in the human postmortem tissue across the lifespan closely resembled that of the truncated DISC1 variants, suggesting the possibility of interactions between these proteins in the human brain. Our results suggest that complexes of full-length DISC1 with truncated DISC1 variants may result in cellular disturbances critical to DISC1 function.
大量的遗传连锁和关联报告表明精神分裂症相关基因（DISC1）与精神疾病有关。苏格兰家族易位，预计编码一个 C 端截断的蛋白质，提示短异构体参与精神障碍的病理生理学。我们最近报道了 DISC1 基因的复杂选择性剪接模式，并发现精神分裂症患者和风险相关等位基因携带者的大脑中短异构体表达过度。对替代 DISC1 异构体的蛋白-蛋白相互作用的研究可能为截断形式在精神疾病中过度表达的功能后果提供信息。用人类表位标记的 DISC1 变体和表位标记的 NDEL1、FEZ1、GSK3β 和 PDE4B 构建体瞬时共转染人胚肾（HEK293）细胞。免疫共沉淀实验表明，所有截断的 DISC1 变体都与全长 DISC1 形成复合物。短 DISC1 剪接变体 LΔ78、LΔ3 和 Esv1 与 NDEL1 和 PDE4B 蛋白的结合减少或没有，但与 FEZ1 和 GSK3β 完全相互作用。GSK3β 在人类死后组织中的时间表达模式在整个生命过程中与截断的 DISC1 变体非常相似，这表明这些蛋白质之间在人类大脑中可能存在相互作用。我们的结果表明，全长 DISC1 与截断的 DISC1 变体的复合物可能导致与 DISC1 功能关键的细胞紊乱。
