Genetic and Pharmacological Evidence for Schizophrenia-Related Disc1 Interaction With GSK-3
Genetic and Pharmacological Evidence for Schizophrenia-Related Disc1 Interaction With GSK-3
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DOI：
10.1002/syn.20839
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发表时间：
2011-03-01
期刊：
影响因子：
2.3
通讯作者：
Roder, John C.
中科院分区：
文献类型：
--
作者：
Lipina, Tatiana V.;Kaidanovich-Beilin, Oksana;Roder, John C.
最近的研究发现，精神分裂症-1中断(DISC1)是与精神分裂症相关的一种强烈的遗传危险因素。此前，我们曾报道过DISC1基因第二外显子[氨基酸第100位亮氨酸到脯氨酸]的突变会导致小鼠精神分裂症相关行为的发展。糖原合成酶-3(GSK-3)是一种丝氨酸/苏氨酸蛋白激酶，与DISC1(aA1-220)的N-末端区域相互作用，是精神分裂症病因学的重要下游成分。在这里，我们第一次证明了GSK-3的药物和遗传失活逆转了前脉冲抑制和潜在的抑制缺陷，并使DISC1-L100P突变体的过度活性正常化。与这些观察结果平行，DISC1-L100P突变体中DISC1与GSK-3α和β之间的相互作用减少。我们的数据为DISC1和GSK-3之间与精神病理学有关的分子联系提供了遗传、生化和行为证据，并强调了错义突变在剖析神经疾病潜在的和复杂的分子机制方面的价值。Synapse 65：234-248,2011。(C)2010年Wiley-Liss公司
Recent studies have identified disrupted-in-schizophrenia-1 (DISC1) as a strong genetic risk factor associated with schizophrenia. Previously, we have reported that a mutation in the second exon of the DISC1 gene [leucine to proline at amino acid position 100, L100P] leads to the development of schizophrenia-related behaviors in mice. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase that interacts with the N-terminal region of DISC1 (aa 1-220) and has been implicated as an important downstream component in the etiology of schizophrenia. Here, for the first time, we show that pharmacological and genetic inactivation of GSK-3 reverse prepulse inhibition and latent inhibition deficits as well as normalizing the hyperactivity of Disc1-L100P mutants. In parallel to these observations, interaction between DISC1 and GSK-3 alpha and beta is reduced in Disc1-L100P mutants. Our data provide genetic, biochemical, and behavioral evidence for a molecular link between DISC1 and GSK-3 in relation to psychopathology and highlights the value of missense mutations in dissecting the underlying and complex molecular mechanisms of neurological disorders. Synapse 65:234-248, 2011. (C) 2010 Wiley-Liss, Inc.