Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders
Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders
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DOI：
10.1016/j.mcn.2003.09.009
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发表时间：
2004-01-01
影响因子：
3.5
通讯作者：
Whiting, PJ
中科院分区：
文献类型：
--
作者：
Brandon, NJ;Handford, EJ;Whiting, PJ
精神分裂症断裂基因1（DISC1）因被平衡的t(1;11)(q42;q14)易位破坏而被确定为精神分裂症的一个潜在易感基因，该易位已被证明在一个苏格兰大家族中与主要精神疾病共分离。我们已经证明，DISC1与Nudel存在于一个受神经发育调控的蛋白质复合物中。该复合物在胚胎第17天（E17）和出生后早期含量丰富，但在成年期大幅减少。先前已证明Nudel与人类无脑回畸形相关基因Lis1结合。关键的是，我们表明由苏格兰易位产生的预测肽产物去除了与Nudel相互作用的结构域。DISC1通过一个亮氨酸拉链结构域与Nudel相互作用，并结合到Nudel上一个新的DISC1相互作用结构域，该结构域独立于Lis1结合位点。我们表明Nudel能够作为DISC1和Lis1之间的桥梁，从而形成一个三聚体复合物。Nudel被认为在神经元迁移中起作用，再加上DISC1 - Nudel复合物含量在发育过程中的变化，可能暗示有缺陷的DISC1 - Nudel复合物是精神分裂症的一个神经发育病因。（C）2003爱思唯尔公司。保留所有权利。
Disrupted In Schizophrenia 1 (DISCI) was identified as a potential susceptibility gene for schizophrenia due to its disruption by a balanced t(1;11) (q42;q14) translocation, which has been shown to cosegregate with major psychiatric disease in a large Scottish family. We have demonstrated that DISCI exists in a neurodevelopmentally regulated protein complex with Nudel. The complex is abundant at E17 and in early postnatal life but is greatly reduced in the, adult. Nudel has previously been shown to bind Lis1, a gene underlying lissencephaly in humans. Critically, we show that the predicted peptide product resulting from the Scottish translocation removes the interaction domain for Nudel. DISCI interacts with Nudel through a leucine zipper domain and binds to a novel DISC1-interaction domain on Nudel, which is independent from the Lis1 binding site. We show that Nudel is able to act as a bridge between DISCI and Lis1 to allow formation of a trimolecular complex. Nudel has been implicated to play a role in neuronal migration, together with the developmental variation in the abundance of the DISC1-Nudel complex, may implicate a defective DISCI-Nudel complex as a neurodevelopmental cause of schizophrenia. (C) 2003 Elsevier Inc. All rights reserved.