Molecular Biology of Nervous Disorders caused by Amyloid

淀粉样蛋白引起的神经紊乱的分子生物学

• 批准号: 04404027
• 负责人: SAKAKI Yoshiyuki
• 金额: $ 8万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (A)
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-04404027/
• 关键词: Amyloidosis; Alzheimer's disease; Transthyretin; Beta amyloid; Transgenic mice; X-ray crystallography; Genetic disease

We have studied on familial amyloidotic polyneuropathy(FAP)and Alzheimer's disease(AD)FAP : we produced large amount of recombinant Met-30 type transthyretin which causes type IFAP, and crystallized it. The TTR crystal was analyzed by X-ray diffraction in collaboration with Drs Collin Blake and Maria Joao Saraiva. The results showed that Cys-recidue at the position 10 was free in the Met-30 TTR, While it interacted with the amino acid recidue at 57 in the wild type TTR.We suggested that the intermolecular S-S bridge formation may trigger the amyloid formation. Transgenic mice study on this hypothesis is in progress.AD : We constructed transgenic mice carrying NFS promoter-App 717 varrant fusion gene and NSF promoter-APP C-100 fusion gene.Those mice showed high expression of the transgenes at mRNA level but no pathological abnormality was observed at the stage of 12 months old.

我们对家族性淀粉样多发性神经病（FAP）和阿尔茨海默病（AD）FAP进行了研究：大量制备了引起IFAP的Met-30型转甲状腺素蛋白，并将其结晶，与柯林布莱克和玛丽亚若昂Saraiva博士合作，对TTR晶体进行了X射线衍射分析。结果表明，Met-30 TTR中第10位的Cys残基是游离的，而野生型TTR中第57位的Cys残基与其相互作用，提示分子间S-S桥的形成可能是淀粉样蛋白形成的触发因素。AD：我们构建了NFS启动子-APP 717 varrant融合基因和NSF启动子-APP C-100融合基因的转基因小鼠，在12月龄时，转基因小鼠在mRNA水平有高表达，但未观察到病理学异常。

项目成果

A.Iwaki et al.: "Accumulation of αβ-crystallin in brains of patients with Alexander's disease is rot dua to an abnormality of the 5'-flanking and coding sequence of the genomic DNA" Neuroscience Letters. 140. 89-92 (1992)

A. Iwaki 等人：“由于基因组 DNA 5 侧翼和编码序列的异常，亚历山大病患者大脑中 αβ-晶状体蛋白的积累发生了变化”《神经科学快报》140. 89-92 (1992)。 ）

I.L.Alves et al.: "Amyloidogenic and non-amyleidogenic transthyretin Asn 90 variants" Clin Genet. 42. 27-30 (1992)

I.L.Alves 等人：“致淀粉样蛋白和非淀粉样蛋白转甲状腺素蛋白 Asn 90 变体”Clin Genet。

R.IZUMI, et al.: "Positive and negative regulatory elements for the expression of the Alzheimer's disease amyloid precursor-encoding gene in mouse." GENE.112. 189-195 (1992)

R.IZUMI 等人：“小鼠阿尔茨海默病淀粉样蛋白前体编码基因表达的正向和负向调节元件。”

A.Iwaki, et al.: "Accumulation of alpha B-crystall in brains of patients with Alexander's disease is not due to an abnormality of 5'-flanking and coding sequence of the genomic DNA." Neuroscience Letters.140. 89-92 (1992)

A.Iwaki 等人：“亚历山大病患者大脑中 α B 晶体的积累并不是由于基因组 DNA 5 侧翼和编码序列的异常造成的。”

T.Yamada et al: "Neuron-specific splicing of the Alzheimer amyloid precursor protein gene in a mini-gene system." Bioch.Biophys.Res.Commun.195. 442-448 (1993)

T.Yamada 等人：“小基因系统中阿尔茨海默病淀粉样蛋白前体蛋白基因的神经元特异性剪接。”