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

舞蹈症棘红细胞增多症基因与精神疾病关系的研究

基本信息

批准号：
14370291
负责人：
SANO Akira
金额：
$ 6.78万
依托单位：
Kagoshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

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.

舞蹈病棘红细胞增多症是一种常染色体隐性遗传的神经退行性疾病，在脑病理学中有报道其尾状核和黑质的选择性变性。最近，我们已经确定了基因，CHAC编码一种新的蛋白质，chorein，其中一个缺失突变被发现在日本CHAC家庭。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，然后通过基因打靶技术将对应于人类疾病突变的#60-61外显子缺失导入CHAC模型小鼠。小鼠进入老年后开始出现运动障碍和棘红细胞增多。在行为学观察中，以移动距离表示的自发活动显著减少，并且在社会互动测试中，模型小鼠的接触时间显著减少。脑组织病理学观察显示纹状体神经元凋亡和胶质增生，谷氨酸脱羧酶免疫反应阳性神经元和纤维及酪氨酸羟化酶免疫反应阳性纤维减少。在黑质，胶质细胞增生，尤其是在网状部，导致减少酪氨酸羟化酶免疫反应神经元，谷氨酸脱羧酶免疫反应神经元和纤维和P物质免疫反应纤维。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良好的模型系统。