Ishizuka Koko, Paek Matt, Kamiya Atsushi, Sawa Akira
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Biol Psychiatry. 2006 Jun 15;59(12):1189-97. doi: 10.1016/j.biopsych.2006.03.065.
Disrupted-In-Schizophrenia-1 (DISC1) is a promising candidate gene for schizophrenia (SZ) and bipolar disorder (BP), but its basic biology remains to be elucidated. Accumulating genetic evidence supports that DISC1 is associated with some aspects of cognitive functions relevant to SZ and BP. Here, we provide a summary of the current updates in biological studies of DISC1. Disrupted-In-Schizophrenia-1, preferentially expressed in the forebrain, has multiple isoforms with potential posttranslational modifications. Disrupted-In-Schizophrenia-1 protein occurs in multiple subcellular compartments, which include the centrosome, microtubule fractions, postsynaptic densities, actin cytoskeletal fractions, the mitochondria, and the nucleus. Recent studies have clarified that DISC1 mediates at least centrosome-dynein cascade and cyclic adenosine monophosphate (cAMP) signaling. Furthermore, both cytogenetic and cell biological studies consistently suggest that an overall loss of DISC1 function (either haploinsufficiency or dominant-negative, or both) may be associated with SZ and BP. On the basis of these findings, production of DISC1 genetically engineered mice is proposed as a promising animal model for SZ and BP. Several groups are currently generating DISC1 mice and starting to characterize them. In this review, the advantages and disadvantages of each animal model are discussed.
精神分裂症相关基因1（DISC1）是精神分裂症（SZ）和双相情感障碍（BP）颇具潜力的候选基因，但其基本生物学特性仍有待阐明。越来越多的遗传学证据支持DISC1与一些与SZ和BP相关的认知功能方面有关。在此，我们总结了DISC1生物学研究的当前进展。精神分裂症相关基因1在前脑优先表达，有多种异构体且可能存在翻译后修饰。精神分裂症相关基因1蛋白存在于多个亚细胞区室，包括中心体、微管部分、突触后致密物、肌动蛋白细胞骨架部分、线粒体和细胞核。最近的研究已阐明，DISC1至少介导中心体 - 动力蛋白级联反应和环磷酸腺苷（cAMP）信号传导。此外，细胞遗传学和细胞生物学研究均一致表明，DISC1功能的全面丧失（单倍剂量不足或显性负性，或两者兼有）可能与SZ和BP相关。基于这些发现，提出构建DISC1基因工程小鼠作为SZ和BP颇具前景的动物模型。目前有几个研究小组正在培育DISC1小鼠并开始对其进行特性描述。在本综述中，讨论了每种动物模型的优缺点。
