Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics

被引:128
作者
Abedini, Andisheh [1 ]
Plesner, Annette [2 ,3 ,6 ]
Cao, Ping [4 ]
Ridgway, Zachary [4 ]
Zhang, Jinghua [1 ]
Tu, Ling-Hsien [4 ]
Middleton, Chris T. [5 ,7 ]
Chao, Brian [1 ]
Sartori, Daniel J. [1 ]
Meng, Fanling [4 ]
Wang, Hui [4 ]
Wong, Amy G. [4 ]
Zanni, Martin T. [5 ]
Verchere, C. Bruce [2 ,3 ]
Raleigh, Daniel P. [4 ]
Schmidt, Ann Marie [1 ]
机构
[1] NYU, Sch Med, Dept Med, Diabetes Res Program,Div Endocrinol Diabet & Meta, New York, NY 10003 USA
[2] Univ British Columbia, Dept Pathol & Lab Med, Child & Family Res Inst, Vancouver, BC, Canada
[3] Univ British Columbia, Dept Surg, Vancouver, BC, Canada
[4] SUNY Stony Brook, Dept Chem, Stony Brook, NY 11794 USA
[5] Univ Wisconsin, Dept Chem, Madison, WI 53706 USA
[6] Novo Nordisk AS, Bagsvaerd, Denmark
[7] Phase Tech Spect Inc, Madison, WI USA
基金
美国国家卫生研究院;
关键词
ENDOPLASMIC-RETICULUM STRESS; ALPHA-SYNUCLEIN OLIGOMERS; BETA-CELL APOPTOSIS; FIBRIL FORMATION; DIABETES-MELLITUS; HUMAN AMYLIN; AROMATIC INTERACTIONS; MEMBRANE DISRUPTION; NLRP3; INFLAMMASOME; PROTEIN OLIGOMERS;
D O I
10.7554/eLife.12977
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Islet amyloidosis by IAPP contributes to pancreatic beta-cell death in diabetes, but the nature of toxic IAPP species remains elusive. Using concurrent time-resolved biophysical and biological measurements, we define the toxic species produced during IAPP amyloid formation and link their properties to induction of rat INS-1 beta-cell and murine islet toxicity. These globally flexible, low order oligomers upregulate pro-inflammatory markers and induce reactive oxygen species. They do not bind 1-anilnonaphthalene-8-sulphonic acid and lack extensive beta-sheet structure. Aromatic interactions modulate, but are not required for toxicity. Not all IAPP oligomers are toxic; toxicity depends on their partially structured conformational states. Some anti-amyloid agents paradoxically prolong cytotoxicity by prolonging the lifetime of the toxic species. The data highlight the distinguishing properties of toxic IAPP oligomers and the common features that they share with toxic species reported for other amyloidogenic polypeptides, providing information for rational drug design to treat IAPP induced beta-cell death.
引用
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页数:28
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