Cysteine 10 is a key residue in amyloidogenesis of human transthyretin Va130Met

Type I familial amyloidotic polyneuropathy (FAP), a systemic amyloidosis, is characterized by aggregation of variant transthyretin (TTR Val30Met) into stable, insoluble fibrils. This aggregation is caused by genetic and environmental factors. Genetic factors have been studied extensively. However, little is known about environmental or physiological factors involved in the disease process, and their identification may be important for development of effective treatment. Xray crystallography of normal and amyloidogenic human TTR Val30Met in type I FAP showed that the -SH side chain of cysteine at position 10 (Cys10) forms a hydrogen bond with Gly57 in normal TTR but not in TTR Val30Met. This result suggests a crucial role for the free Cys10 residue and possible involvement of physiological factors affecting Cys residue reactivity in TTR amyloidogenesis. To analyze amyloidogenesis in vivo, our group generated murine FAP models by transgenic technology, with human TTR Val30Met. The three lines of transgenic mice expressed amyloidogenic mutant TTR (Cys10/Met30), wild-type TTR (Cys10/Val30), and artificial Cys-free mutant TTR (Ser10/Met30). Histochemical. investigation showed deposition of amyloid derived from human TTR only in amyloidogenic mutant TTR (Cys10/Met30) mice. Thus, the -SH residue in Cys10 plays a crucial role in TTM Val30Met amyloidogenesis in vivo. These data suggest the possibility of innovative treatment via physiological factors modulating Cys10 residue reactivity.