Mutations of DISC1 (disrupted-in-schizophrenia 1) have been associated with major psychiatric disorders. Despite the hundreds of DISC1-binding proteins reported, almost nothing is known about how DISC1 interacts with other proteins structurally to impact human brain development. Here we solved the high-resolution structure of DISC1 C-terminal tail in complex with its binding domain of Ndel1. Mechanistically, DISC1 regulates Ndel1's kinetochore attachment, but not its centrosome localization, during mitosis. Functionally, disrupting DISC1/Ndel1 complex formation prolongs mitotic length and interferes with cell-cycle progression in human cells, and it causes cell-cycle deficits of radial glial cells in the embryonic mouse cortex and human forebrain organoids. We also observed similar deficits in organoids derived from schizophrenia patient induced pluripotent stem cells (iPSCs) with a DISC1 mutation that disrupts its interaction with Ndel1. Our study uncovers a new mechanism of action for DISC1 based on its structure, and it has implications for how genetic insults may contribute to psychiatric disorders.

中文翻译：

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DISC1在有丝分裂过程中通过调节Ndel1 / Nde1的线粒体附着调节神经发生。

DISC1突变（精神分裂症1）已与主要的精神疾病有关。尽管报道了成百上千的DISC1结合蛋白，但关于DISC1如何与其他蛋白在结构上影响人类大脑发育的相互作用几乎一无所知。在这里，我们解决了DISC1 C末端尾巴的复杂结构及其Ndel1结合域的复杂结构。从机制上讲，DISC1在有丝分裂过程中调节Ndel1的动粒附着，但不调节其中心体定位。在功能上，破坏DISC1 / Ndel1复合物的形成会延长有丝分裂的长度，并干扰人细胞中的细胞周期进程，并且会导致胚胎小鼠皮层和人前脑类器官的星形胶质细胞的细胞周期不足。我们还观察到源自精神分裂症患者诱导的多能干细胞（iPSC）的类器官的类似缺陷，该干细胞具有DISC1突变，破坏了它与Ndel1的相互作用。我们的研究基于其结构揭示了DISC1的新作用机制，并且它对遗传损伤如何导致精神疾病具有重要意义。