DEVELOPMENT OF PREVENTION METHOD USING A MOUSE MODEL FOR FAMILIAL AMYLOIDOTIC POLYNEUROPATHY

家族性淀粉样多发性神经病（FAP）是一种常染色体显性遗传疾病，其特征是纤维状淀粉样蛋白的细胞外沉积和显著的外周神经受累。在大多数I型FAP患者中，淀粉样蛋白沉积物的主要成分是在氨基酸位置30（hMet 30）处甲硫氨酸取代缬氨酸的变体TTR。迄今为止，所有FAP患者都被发现携带至少一种突变基因，这表明这种疾病主要是由突变TTR基因的存在引起的。然而，FAP中淀粉样蛋白沉积的病理过程仍然完全未知。因此，肝移植是唯一有效的治疗方法。我们以前证明了携带人Met 30 TTR基因的小鼠系在除了外周神经组织之外的FAP患者的各种组织中发生淀粉样蛋白沉积。使用这些转基因小鼠，我们证明了遗传和环境因素都参与了淀粉样蛋白的发展。如在 ...更多信息 肠道植物群可能是影响转基因小鼠生长的重要因素之一，我们建立了含有SPF小鼠或普通小鼠植物群的转基因小鼠品系。此外，我们试图研究Cys 10的作用，因为在相邻的transthyretin分子上Cys残基之间的二硫键被认为是淀粉样蛋白生成的重要因素。我们生产了三种转基因小鼠品系，它们携带Cys 10-Val 30、Cys 10-Met 30或Ser 10-Met 30中的一种转基因，以测试这种可能性。正如预期的那样，在23只携带正常淀粉样蛋白Cys 10-Val 30的转基因小鼠中没有观察到淀粉样蛋白沉积。然而，19只携带突变基因Cys 10-Met 30的小鼠中有6只观察到淀粉样蛋白。有趣的是，我们发现淀粉样蛋白沉积只有1 37转基因小鼠携带Ser 10-Met 30。这些结果清楚地表明30位半胱氨酸在淀粉样蛋白形成中起重要作用。基于这一结果，我们正在分析抗氧化剂是否可以减少转基因小鼠模型中淀粉样蛋白的数量。少

Familial amyloidotic polyneuropathy (FAP) is an autosomal, dominant disorder characterized by extracellular deposition of fibrillar amyloid protein and prominent peripheral nerve involvement. In most patients with Type I FAP, the major component of the amyloid deposits is a variant TTR with a substitution of methionine for valine at amino acid position 30 (hMet30). All FAP patients so far examined have been found carry at least one mutant gene, suggesting that this disease is mainly caused by the presence of the mutant TTR gene. However, the pathologic processes of amyloid deposition in FAP remain totally unknown. Thus, liver transplantation is the only effective treatment. We previously demonstrated that a mouse line carrying a human Met30 TTR gene developed amyloid deposition in various tissues as in FAP patients except peripheral nervous tissues. Using these transgenic mice, we demonstrated that both genetic and environmental factors are involved in the development of amyloid. As in … More testinal flora was suggested to be one of these factors, we established transgenic mouse lines having either flora from SPF mouse or conventional mouse. In addition, we tried to investigate the role of Cys10, because the disulfide bond between Cys residues on adjuscent trasnthyretin molecules was suggested to be important for amyloidogenesis. We produced three lines of transgenic mouse lines carrying one of the transgenes, Cys10-Val30, Cys10-Met30, or Ser10-Met30 to test this possibility. As expected, no amyloid deposition was observed in 23 transgenic mice carrying the noramal allel, Cys10-Val30. However, amyloid was observed in 6 out of 19 mice carrying the mutant gene, Cys10-Met30. Interestingly, we found amyloid deposits only in 1 out of 37 transgenic mice carrying Ser10-Met30. These result clearly suggest that cystein at position 30 plays an important role in amyloid formation. Based on this result, we are analyzing whether anti-oxidant can reduce the amount of amyloid in a transgenic mouse model. Less