Study on the relation between chorea-acanthocytosis gene and psychiatric disorders

舞蹈病-棘细胞增多症（CHAC）是一种常染色体隐性遗传的遗传性神经退行性疾病，在脑部病理中报道了尾状核和黑质的选择性变性。最近，我们在日本CHAC家族中发现了一个缺失突变的基因，CHAC编码一种新的蛋白质，舞蹈蛋白。在本研究中，我们克隆了小鼠CHAC cDNA，鉴定了该基因的外显子-内含子结构，然后通过基因靶向技术制备了CHAC模型小鼠，引入了与人类疾病突变相对应的#60-61外显子缺失。老年小鼠开始出现运动障碍和棘细胞增多症。在行为观察中，以移动距离表示的运动活动显著减少，在社会互动测试中，模型小鼠的接触时间显著减少。脑组织病理组织化学观察显示纹状体出现神经元凋亡和胶质瘤，导致谷氨酸脱羧酶免疫反应神经元和纤维以及酪氨酸羟酶免疫反应纤维减少。在黑质中，神经胶质瘤主要发生在网状部，导致酪氨酸羟酶免疫反应神经元、谷氨酸脱羧酶免疫反应神经元和纤维以及p物质免疫反应纤维减少。这些发现与其他地方报道的人类结果完全一致。因此，chac模型小鼠为研究人类疾病提供了一个良好的模型系统。

Chorea-acanthocytosis (CHAC) is a hereditary neurodegenerative disorder with autosomal recessive transmission, in which selective degeneration of caudate nucleus and substantia nigra has been reported in brain pathology. Recently, we have identified the gene, CHAC encoding a novel protein, chorein in which a deletion mutation was found in Japanese CHAC families. In the present study, we have cloned the mouse CHAC cDNA, identified the exon-intron structures of the gene, and then produced a CHAC-model mouse introducing #60-61 exons-deletion corresponding to a human disease mutation by gene-targeting technique. The mice began to show motor disturbance and acanthocytosis after becoming old age. In behavioral observations, locomotor activity expressed as moving distance was significantly decreased, and at social interaction test the contact time was decreased significantly in the model mice. In brain pathology, histochemical observation revealed that neuronal apoptosis and gliosis occurred in the striatum, which lead to the decrease in glutamic acid decarboxylase-immunoreactive neurons and fibers and tyrosine hydroxylase-immunoreactive fibers. In substantia nigra, gliosis was observed especially in the pars reticulata, leading to decrease in tyrosine hydroxylase-immunoreactive neurons, glutamic acid decarboxylase-immunoreactive neurons and fibers and substance P-immunoreactive fibers. These findings are completely consistent with the human results reported elsewhere. The CHAC-model mouse therefore provides a good model system to study the human disease.