Abstract:
:Islet amyloidosis by IAPP contributes to pancreatic β-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 β-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 β-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 β-cell death.
journal_name
Elifejournal_title
eLifeauthors
Abedini A,Plesner A,Cao P,Ridgway Z,Zhang J,Tu LH,Middleton CT,Chao B,Sartori DJ,Meng F,Wang H,Wong AG,Zanni MT,Verchere CB,Raleigh DP,Schmidt AMdoi
10.7554/eLife.12977subject
Has Abstractpub_date
2016-05-23 00:00:00issn
2050-084Xjournal_volume
5pub_type
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