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Biochemical, cell biological and proteomical characterization of dysfunctional and posttranslationally modified DISC1 protein

功能失调和翻译后修饰的 DISC1 蛋白的生化、细胞生物学和蛋白质组学表征

基本信息

批准号：
153683525
负责人：
Professor Dr. Carsten Korth
金额：
--
依托单位：
Institut für Neuropathologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2009
资助国家：
德国
起止时间：
2008-12-31 至 2012-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/153683525?language=en
关键词：
Biochemical cell biological proteomical characterization

项目摘要

DISC1 has been demonstrated to be genetically linked to familial chronic mental diseases (CMD) of mixed phenotypes, like schizophrenia or the affective disorders. While the biology of mutant DISC1 has been modeled in vitro and in vivo, a mechanism of how full length DISC1 could be dysfunctional in cases of sporadic CMD has remained elusive. The Korth lab has shown that a subset of cases with sporadic CMD can be characterized by the occurrence of insoluble DISC1 in brains. Insoluble DISC1 becomes dysfunctional in terms of lack of binding to NDEL1, a major ligand for executing neuronal functions. Here, we propose to further characterize the conditions under which DISC1 aggregates in cell models and to dissect the conditions under which DISC1 multimers generated in vivo and, eventually, become dysfunctional; this includes the identification of aggregation-favoring polymorphism combinations, transcripts or -degradation products, effects of cellular stressors, cytosolic dopamine, and the efect of steroid hormones. The ultimate goal is to investigate how the DISC1 protein, including when it is posttranslationally modified, is associated with behavioral and neurochemical phenotypes and, thereby, link the DISC1 protein to sporadic cases of CMD.

DISC1已被证明与混合表型的家族性慢性精神疾病（CMD）有遗传联系，如精神分裂症或情感障碍。虽然突变体DISC1的生物学已经在体外和体内建立了模型，但在散发性CMD的情况下，全长DISC1如何功能失调的机制仍然难以捉摸。Korth实验室已经表明，散发性CMD病例的一个子集可以以大脑中不溶性DISC1的发生为特征。不溶性DISC1由于缺乏与NDEL1结合而变得功能失调，NDEL1是执行神经元功能的主要配体。在这里，我们建议进一步表征DISC1在细胞模型中聚集的条件，并剖析DISC1多聚体在体内产生并最终变得功能失调的条件；这包括鉴定有利于聚集的多态性组合、转录物或降解产物、细胞应激源的作用、胞质多巴胺和类固醇激素的作用。最终目标是研究DISC1蛋白如何与行为和神经化学表型相关，包括何时进行翻译后修饰，从而将DISC1蛋白与散发性CMD病例联系起来。