Generation and biochemical characterization of a transgenic rat model for sporadic mental disease by overexpressing full length DISC1

DISC1已被证明与混合表型的家族性慢性精神疾病(CMD)有关，如精神分裂症或情感障碍。导致遗传性CMD的突变已经成功地通过在几个反映CMD的神经病理和行为表型的转基因小鼠系中的表达来模拟。然而，大多数CMD病例不是遗传的。为了研究非突变、全长DISC1在散发性CMD病例中的发病机制，对翻译后修饰进行了分析。我们证明，散发性CMD的一个子集可以通过大脑中出现不溶性DISC1来表征。难溶的DISC1由于缺乏与NDEL1的结合而功能失调，NDEL1是执行神经元功能的主要配体。在这里，我们建议通过在普恩蛋白启动子的控制下过表达人全长DISC1来建立一个转基因大鼠模型作为散发性CMD的模型。其想法是，类似于阿尔茨海默氏症S和亨廷顿S病的转基因动物模型，这种致病蛋白的过度表达可能会导致体内出现突变和不可溶的蛋白物种，导致类似于人类疾病的临床表型。转基因大鼠模型的优势将得到充分利用，例如在神经病理和成像研究、组织取样和更具差异性的行为测试中具有更好的解剖分辨率。

DISC1 has been demonstrated to be genetically linked to familial chronic mental diseases (CMD) of mixed phenotypes, like schizophrenia or the affective disorders. The mutation causing genetic CMD has been successfully modeled by expression in several transgenic mouse lines reflecting neuropatholgoical and behavioral phenotypes of CMD. However, the majority of CMD cases are not genetic. To investigate pathomechanisms in non-mutant, full length DISC1 in sporadic cases of CMD, posttranslational modifications were analyzed. We demonstrated that a subset of cases with sporadic CMD could 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 generate a transgenic rat model as a model for sporadic CMD by overexpressing human full length DISC1 under the control of the prion protein promotor. The idea is that, similar to transgenic animal models of Alzheimer s and Huntington s dissease, overexpression of the disease-causing protein may lead to mutlimeric and insoluble protein species in vivo causing a clinical phenotype similar to that of the human disease. The advantages of a transgenic rat model, like better anatomical resolution for neuropathological and imaging studies, tissue sampling and more differentiated behavioral tests will be fully exploited.