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  • 09월 04일 17시 이후 : 초록수정 불가능, 일정확인 및 검색만 가능

제114회 대한화학회 학술발표회, 총회 및 기기전시회 안내 A thiol-reactive rosamine derivative inhibits tau aggregation by blocking tau intermolecular disulfide bond formation

2014년 8월 28일 16시 54분 08초
BIO.P-648 이곳을 클릭하시면 발표코드에 대한 설명을 보실 수 있습니다.
10월 15일 (수요일) 16:00~19:00
저자 및
HAQUE MD MAMUNUL, 하형호1, 김윤경2,*
한국과학기술연구원(KIST) 뇌의약연구단, Korea
1순천대학교 약학대학 약학과, Korea
2한국과학기술연구원(KIST) 뇌과학연구소/뇌의약연구단, Korea
The primary function of tau is to promote and stabilize microtubule assembly in neuronal axons. When pathologically modified, tau dissociates from microtubules and become insoluble aggregates called neurofibrillary tangles (NFTs). The NFTs are made up of paired helical filaments (PHFs) that constitute the defining characteristics of Alzheimer’s disease, Parkinson’s disease and many other neurodegenerative disorders collectively called tauopathies. The PHFs are consisted of aggregated tau. Tau aggregation is a multistep process with diverse intermediate stages. To become a susceptible intermediate for aggregation, tau protein undergoes a series of post-translational modifications. Among diverse modifications, oxidation state of the protein has been shown significant role to influence tau aggregation tendency. Full length human tau contains two cysteine residues (Cys291 and Cys322) in its amino acid. These cysteines can form both intra- and inter-molecular disulfide bonds. During in vitro tau aggregation, tau-tau disulfide-linked dimers form first that serve as the seeds for higher order aggregates. So, intermolecular disulfide linkage is important in the generation of tau aggregates. Here we envision that prevention of tau disulfide bond formation with a small molecule would inhibit the generation of tau aggregates. We have tested a bunch of chemical compounds for their ability to inhibit the assembly of tau into aggregated filaments in vitro. The exclusive criteria of our tested compounds are the thiol reactivity and they also possess the fluorescence properties. In particular, two novel compounds were proved effective in the inhibition of tau filament formation with IC50 values in the low micromolar range. Therefore, this finding provides a new strategy for inhibiting tau aggregation by targeting tau intermolecular disulfide cross-links.