研究発表を行った学会； 20th IUBMB International Congress
　　　２００６年６月１８日〜２３日 (Kyoto)
タイトル； Inhibition of intracellular tetramerization targets amyloidogenic transthyretin variants to proteosomal degradation.
発表者；薄　聖子　氏
　　　（熊本大学　大学院医学薬学研究部　遺伝子機能応用学分野）
Abstract；
Small molecules are shown to stabilize transthyretin (TTR) in vitro but their effectivity in mammalian cells is unknown. We show here that the small molecules thyroxine and diflunisal have selective effect on amyloidogenic TTRs in vivo. They slightly decreased the monomer levels of V30M and L55P TTRs in the cell media but not that of D18G, A25T and E54K TTRs, implying that the therapeutic use of small molecules as TTR stabilizers might be limited. The secretion of amyloidogenic variant TTRs contributes to the pathogenesis of amyloidosis because of their tendency to dissociate into monomers that are prone to aggregate in the extracellular environment. Thus, a possible therapeutic approach is to promote their intracellular degradation. We determined that monomeric mutation (F87M/L110M) introduced into TTRs (M-TTRs) prevented the secretion of amyloidogenic variants but not of wild-type or non-amyloidogenic TTRs, indicating that for destabilized TTR variants, tetramerization might be necessary for secretion. Immunofluorescence analyses revealed that the amyloidogenic M-TTRs were retained in the ER and that ER retention leads to ER-associated degradation of M-TTR variants. These data suggest that the clearance of disease-causing TTR variants in the ER by proteosomal degradation could be enhanced through inhibition of their intracellular tetramerization.