アクティブボード・２０１８年　３月
　　　　　・・・・・２０１８年　３月　１日作成・・・・・
研究発表を行った学会；
　　　2017年度　生命科学系学会合同年次大会 (ConBio2017)
　　　2017年12月 6日〜 9日（神戸）
タイトル；Intracellular behavior of TTR-FA causative protein transthyretin in the presence of compound JS-K discovered by high throughput screening.
発表者；今井　快樹　氏
　　　（熊本大学　大学院生命科学研究部　遺伝子機能応用学分野）
要旨；
Familial amyloid polyneuropathy (TTR-FAP) is one of the hereditary amyloidosis caused by a point mutation in the human plasma protein, transthyretin (TTR). Amyloid fibrils derived from TTR variants accumulate in peripheral nerves and visceral organs. Suppression of TTR secretion is one of the promising approaches for FAP therapy, so that discover low molecular weight compounds, which can reduce secretion of mutant TTRs is urgently needed. Previously, we demonstrated that the endoplasmic reticulum (ER) quality control system limits the secretion of amyloidogenic monomeric TTR variants, and hypothesized that inhibition of TTR variants secretion through its destablilization in ER prevents disease progression. We performed in vitro fluorescence-based high throughput screening (LOPAC1280). We focused on JS-K that is the candidate compound and evaluated mechanism of suppression of TTR secretion. In the V30M TTR-stable HEK293 cell line, JS-K treatment increased the amount of intracellular TTR but decreased extracellular TTR. Because TTR tetramer structure dissociates into monomers by S-NO modification of the cysteine residue (Cys10) and JS-K is known as an NO donor, we next investigated the effect of JS-K on Cys10Ala TTR mutant. Notably, JS-K treatment had no effect on the amounts of intracellular and extracellular Cys10Ala TTR, suggesting that S-NO modification is involved in JS-K-dependent suppression of TTR secretion. Altogether, we revealed that the TTR-FAP drug candidate compound JS-K induce S-NO modification of TTR and destabilize the tetramer structure of TTR. This raises the possibility that preventing V30M TTR secretion maybe a novel therapeutic approach to TTR-FAP.