2012年11月5日 讯 /生物谷BIOON/ --近日，刊登于国际杂志The FASEB Journal上的一项研究发现或许为理解某些儿童的精神疾病带来了革命性的进展，研究者发现，当一种参与大脑发育的蛋白质SRGAP3处于畸形状态的话，其就会引发小鼠大脑功能障碍，随后就会引发和儿童神经性障碍相似的一些症状表现。由于这种蛋白质在人类机体中有类似的功能，其或许是许多疾病障碍中缺失的一个环节，另外，该蛋白质的发现也可帮助研究者开发新型的以该蛋白质为靶点的疗法。
研究者Dusan说，诸如精神分裂症、脑积水、精神发育迟滞和自闭症等大脑障碍对于儿童和年轻人来说是一种破坏性的疾病。我们希望我们的研究发现可以帮助研究者更好地理解疾病的发病过程以及开发出有效的疗法。
文章中，研究者用SRGAP3蛋白失活的小鼠进行实验，随后研究者比较这种小鼠与正常小鼠的差异，结果显示，SRGAP3蛋白失活的小鼠，其大脑解剖面发生了明显的改变，将会导致其行为类似于精神病人的行为。不同脑功能障碍中涉及的SRGAP3蛋白质表明这些障碍都是相关联的，而且SRGAP3蛋白是大脑发育的一个关键蛋白质。这些脑功能障碍或许是通过SRGAP3蛋白进行相互连接的，因为其都是通过干扰大脑神经系统的发育来产生疾病的。
最终，研究者通过研究结果来从基因、蛋白质乃至细胞信号通力和行为方面来理解大多数精神性疾病的复杂生物过程，这可以帮助研究者开发出新型的靶向疗法。（生物谷Bioon.com）
编译自：Single Protein Targeted as Root Biological Cause of Several Childhood Psychiatric Disorders
doi:10.1096/fj.11-202317
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Srgap3−/− mice present a neurodevelopmental disorder with schizophrenia-related intermediate phenotypes
Robert Waltereit*,†, Uwe Leimer*, Oliver von Bohlen und Halbach‖, Jutta Panke*, Sabine M. Hölter¶, Lillian Garrett¶, Karola Wittig§, Miriam Schneider‡, Camie Schmitt*, Julia Calzada-Wack#, Frauke Neff#, Lore Becker**,††, Cornelia Prehn**, Sergej Kutscherjawy*, Volker Endris‡‡, Claire Bacon‡‡, Helmut Fuchs**, Valérie Gailus-Durner**, Stefan Berger*, Kai Schönig*, Jerzy Adamski**, Thomas Klopstock††, Irene Esposito#§§, Wolfgang Wurst‖‖¶¶##, Martin Hrabě de Angelis**,***, Gudrun Rappold‡‡, Thomas Wieland§ and Dusan Bartsch*,1
Mutations in the SRGAP3 gene residing on chromosome 3p25 have previously been associated with intellectual disability. Genome-wide association studies have also revealed SRGAP3, together with genes from the same cellular network, as risk genes for schizophrenia. SRGAP3 regulates cytoskeletal dynamics through the RHO protein RAC1. RHO proteins are known to be involved in cytoskeletal reorganization during brain development to control processes such as synaptic plasticity. To elucidate the importance of SRGAP3 in brain development, we generated Srgap3-knockout mice. Ten percent of these mice developed a hydrocephalus and died before adulthood. Surviving mice showed various neuroanatomical changes, including enlarged lateral ventricles, white matter tracts, and dendritic spines together with molecular changes, including an increased basal activity of RAC1. Srgap3−/− mice additionally exhibited a complex behavioral phenotype. Behavioral studies revealed an impaired spontaneous alternation and social behavior, while long-term memory was unchanged. The animals also had tics. Lower locomotor activity was observed in male Srgap3−/− only. Srgap3−/− mice showed increased methylphenidate stimulation in males and an impaired prepulse inhibition in females. Together, the results show neurodevelopmental aberration in Srgap3−/− mice, with many of the observed phenotypes matching several schizophrenia-related intermediate phenotypes. Mutations of SRGAP3 may thus contribute to various neurodevelopmental disorders.—Waltereit, R., Leimer, U., von Bohlen und Halbach, O., Panke, J., Hölter, S. M., Garrett, L., Wittig, K., Schneider, M., Schmitt, C., Calzada-Wack, J., Neff, F., Becker, L., Prehn, C., Kutscherjawy, S., Endris, V., Bacon, C., Fuchs, H., Gailus-Durner, V., Berger, S., Schönig, K., Adamski, J., Klopstock, T., Esposito, I., Wurst, W., Hrabě de Angelis, M., Rappold, G., Wieland, T., Bartsch, D. Srgap3−/− mice present a neurodevelopmental disorder with schizophrenia-related intermediate phenotypes.
