Molecular pathogenesis of transmissible spongiform encephalopathy

传染性海绵状脑病的分子发病机制

• 批准号: 08300011
• 负责人: YAMANOUCHI Kazuya
• 金额: --
• 依托单位: Nippon Institute for Biological Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08300011/
• 关键词: prion; scrapie; transmissible spongiform encephalopath; neurological diseases; prion diseases; Creutzfeldt-Jakob disease; スクレイピ-; 牛海綿状脳症

Molecular pathogenesis of prion disease was studied based on the analysis of prion protein (PrP) gene.Several new findings were also obtained from the studies on animal models.Involevement of polymorphisms of PrP gene in the onset of prion disease was indicated, especially in term of correlation of codon 219 with sporadic Creutzfeldt-Jakob disease as a unique feature of Japanese.Correlation of PrP gene mutation with transmission of the disease to mice was also demonstrated.Transgenic mice overexpressing human PrP gene was produced and found to be highly susceptible to CJD.Biochemical profiles of the brain of CJD patient was demonstrated in term of gangliosides.Resistance of PrPSc to proteinase K was shown to correlate with the incubation period of scrapie in mice, and passages in mice brain was suggested to cause increased aggregation of PrPSc.Studies of prion-less neural cells suggested an involvement of apoptosis in the cell death.In vitro model of the conformational change of protein showed temperature-dependent conversion from alpha-helix to beta-sheet.As an animal model of spongiform encephalopathy, zitter rats were studied in terms of zi gene and involvement of super-oxide in pathogenesis.Investigation on spontaneous spongiform encephalopathy in pets and birds could not find such cases.

通过对朊病毒蛋白（PrP）基因的分析，研究了朊病毒病的分子发病机制。在动物模型研究中也获得了一些新的发现。PrP基因多态性与朊病毒病的发病有关，特别是在妊娠期。密码子 219 与日本特有的散发性克雅氏病的相关性。PrP 基因突变与小鼠传播疾病的相关性还证实了过表达人 PrP 基因的转基因小鼠，发现其对克雅氏病高度敏感。克雅氏病患者大脑的生化特征以神经节苷脂的形式得到证明。PrPSc 对蛋白酶 K 的抵抗力与潜伏期相关小鼠瘙痒病的发生，以及小鼠大脑中的传代被认为导致 PrPSc 聚集增加。对无朊病毒的神经细胞的研究表明，细胞凋亡参与了细胞死亡。蛋白质构象变化呈现温度依赖性从α螺旋向β折叠的转变。以zitter大鼠为海绵状脑病动物模型，对zi基因及超氧化物在发病机制中的参与进行研究。自发性海绵状脑病的研究在宠物和鸟类中找不到这样的情况。

项目成果

品川森一: "Characterization of the sheep apolipoprotein E gene and allelic variations of the ApoE gene in scrapie Suffolk sheep" Gene. 208. 131-138 (1998)

Moriichi Shinakawa：“绵羊载脂蛋白 E 基因的特征和萨福克绵羊中 ApoE 基因的等位基因变异”基因。 208. 131-138 (1998)

立石 潤: "プリオンとプリオン病" 共立出版, 116 (1998)

Jun Tateishi：“朊病毒和朊病毒病”共立出版，116（1998）

北本哲元: "Thalamic form of Creutzfeldt-Jakob disease or fatal insomiareport of sporadic case with normal prion protein genotype" Acta Neuropathol.93. 317-322 (1997)

Tetsumoto Kitamoto：“克雅氏病的丘脑形式或具有正常朊病毒蛋白基因型的散发病例的致命性失眠报告”Acta Neuropathol.93（1997）。

北本哲元: "Typing prion isoforms" Nature. 386. 232-233 (1997)

Tetsumoto Kitamoto：“朊病毒亚型的分型”《自然》386. 232-233 (1997)。

北本哲也: "Human prion disease and human prion protein disease" Curr.Topics Micriobiol.Immunol.207. 27-34 (1996)

Tetsuya Kitamoto：“人类朊病毒病和人类朊病毒蛋白病”Curr.Topics Micriobiol.Immunol.207 (1996)。