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Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics.
- Source :
-
ELife [Elife] 2016 May 23; Vol. 5. Date of Electronic Publication: 2016 May 23. - Publication Year :
- 2016
-
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.
- Subjects :
- Amyloidosis therapy
Animals
Cell Survival
Cells, Cultured
Inflammation pathology
Insulin-Secreting Cells physiology
Islets of Langerhans pathology
Mice
Mice, Inbred C57BL
Protein Conformation
Protein Denaturation
Protein Multimerization
Rats
Reactive Oxygen Species analysis
Time Factors
Amyloidogenic Proteins metabolism
Amyloidogenic Proteins toxicity
Amyloidosis physiopathology
Islet Amyloid Polypeptide metabolism
Islet Amyloid Polypeptide toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 2050-084X
- Volume :
- 5
- Database :
- MEDLINE
- Journal :
- ELife
- Publication Type :
- Academic Journal
- Accession number :
- 27213520
- Full Text :
- https://doi.org/10.7554/eLife.12977