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

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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