多聚谷氨酰胺疾病DRPLA小鼠模型的建立、机理研究和药物治疗

发布时间：2018-01-02 02:00

本文关键词：多聚谷氨酰胺疾病DRPLA小鼠模型的建立、机理研究和药物治疗　出处：《复旦大学》2005年博士论文　论文类型：学位论文

【摘要】：齿状核红核苍白球丘脑底核萎缩(dentatorubral-pallidoluysian atrophy，DRPLA)是一种常染色体显性遗传的神经退行性疾病，临床表现有共济失调、震颤、肌肉痉挛、舞蹈症、痴呆等。DRPLA是由atrophin-1基因中编码谷氨酰胺的CAG重复序列的扩增所造成，包含多聚谷氨酰胺扩增的Atrophin-1突变蛋白导致齿状核、红核、苍白球以及丘脑底核等脑区的神经元损伤。为了研究DRPLA的发病机理和治疗方法，我们建立了神经元特异性表达人类突变型Atrophin-1蛋白的转基因小鼠——Atro-118Q。行为学和病理学分析显示，Atro-118Q小鼠基本模拟了DRPLA患者的神经退行性病征，包括：共济失调、震颤等运动缺陷，神经元的核内包涵体以及神经元的胞体萎缩，，说明Atro-118Q小鼠是一种较好的DRPLA小鼠模型。野生型Atrophin-1蛋白的高表达不能减弱Atro-118Q小鼠的神经退行性表型，说明多聚谷氨酰胺扩增的Atrophin-1蛋白所造成的表型可能并不是简单地由突变蛋白的显性负效应(dominant negative effect)所引起的。生化分析显示，在Atro-118Q小鼠的脑组织中，组蛋白乙酰化水平明显降低，提示基因转录的抑制可能与Atro-118Q小鼠的神经退行性表型有关。腹腔注射组蛋白脱乙酰基酶的抑制剂——丁酸钠，能够提高Atro-118Q小鼠脑组织中组蛋白的乙酰化水平，同时缓解了Atro-118Q小鼠的运动缺陷，延长了小鼠的寿命。这一结果为开展DRPLA的药物治疗提供了十分有意义的线索，同时也表明基因转录失调很可能是包括DRPLA在内的多种多聚谷氨酰胺疾病的重要病因之一。 DRPLA的致病基因atrophin-1在进化上具有较高的保守性，编码的蛋白质参与基因转录的调控。为了深入研究atrophin-1基因的功能，我们建立了atrophin-1基因剔除小鼠。atrophin-1~(-／-)小鼠出现脑组织、眼睛等方面的异常表型，对该小鼠的研究将有助于揭示转录调节基因atrophin-1与器官发育以及DRPLA等多聚谷氨酰胺疾病的关系。
[Abstract]:Dentatorubral-pallidoluysian atrophy of the hypothalamic nucleus pallidoluysian of the dentate nucleus red nucleus pallidoluysian. DRPLA is an autosomal dominant neurodegenerative disease characterized by ataxia tremor muscle spasm and chorea. DRPLA is caused by the amplification of CAG repeats encoding glutamine in the atrophin-1 gene. The polyglutamine amplified Atrophin-1 mutant protein causes neuronal damage in the dentate nucleus, red nucleus, globus pallidus and subthalamic nucleus. In order to study the pathogenesis and treatment of DRPLA. We established a neuron-specific transgenic mouse expressing human mutant Atrophin-1 protein Atro-118Q.Behavioral and pathological analysis showed. Atro-118Q mice basically simulated the neurodegenerative symptoms of DRPLA patients, including ataxia, tremor and other motor defects, neuronal inclusion bodies and neuronal cell body atrophy. The high expression of wild-type Atrophin-1 protein can not attenuate the neurodegenerative surface of Atro-118Q mice. Type. These results suggest that the phenotypes of polyglutamine amplified Atrophin-1 proteins may not be simply due to the dominant negative effects of mutant proteins (. Dominant negative effect. biochemical analysis shows. The level of histone acetylation was significantly decreased in Atro-118Q mice. It was suggested that the inhibition of gene transcription might be related to the neurodegenerative phenotype of Atro-118Q mice. Sodium butyrate, an inhibitor of histone deacetylase, was injected intraperitoneally. It can improve the level of acetylation of histone in brain tissue of Atro-118Q mice and alleviate the motor defect of Atro-118Q mice at the same time. The results provide a useful clue to the development of drug therapy for DRPLA. It also suggests that gene transcriptional disorders may be one of the major causes of polyglutamine disease including DRPLA. The pathogenicity gene atrophin-1 of DRPLA is highly conserved in evolution. The encoded protein is involved in the regulation of gene transcription. In order to further study the function of atrophin-1 gene. We established abnormal phenotypes of brain tissue and eyes in atrophin-1 gene knockout mice. The study of this mouse will be helpful to reveal the relationship between transcription regulating gene atrophin-1 and organ development and polyglutamine disease such as DRPLA.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2005
【分类号】：R-332

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