Time-resolved Studies Define the Nature of Toxic IAPP Intermediates, Providing Insight for Anti-amyloidosis Therapeutics

Overview

Journal Elife

Specialty Biology

Date 2016 May 24

PMID 27213520

Citations 81

Authors

Andisheh Abedini

Annette Plesner

Ping Cao

Zachary Ridgway

Jinghua Zhang

Ling-Hsien Tu

Chris T Middleton

Brian Chao

Daniel J Sartori

Fanling Meng

Hui Wang

Amy G Wong

Martin T Zanni

C Bruce Verchere

Daniel P Raleigh

Ann Marie Schmidt

Affiliations

Soon will be listed here.

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.

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References

Cao P, Abedini A, Raleigh D . Aggregation of islet amyloid polypeptide: from physical chemistry to cell biology. Curr Opin Struct Biol. 2012; 23(1):82-9. PMC: 3969731. DOI: 10.1016/j.sbi.2012.11.003. View

Westermark P, Andersson A, Westermark G . Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiol Rev. 2011; 91(3):795-826. DOI: 10.1152/physrev.00042.2009. View

Westermark G, Westermark P, Berne C, Korsgren O . Widespread amyloid deposition in transplanted human pancreatic islets. N Engl J Med. 2008; 359(9):977-9. DOI: 10.1056/NEJMc0802893. View

Ashcroft F, Rorsman P . Diabetes mellitus and the β cell: the last ten years. Cell. 2012; 148(6):1160-71. PMC: 5890906. DOI: 10.1016/j.cell.2012.02.010. View

Wimley W, Creamer T, White S . Solvation energies of amino acid side chains and backbone in a family of host-guest pentapeptides. Biochemistry. 1996; 35(16):5109-24. DOI: 10.1021/bi9600153. View

Milton N, Harris J . Fibril formation and toxicity of the non-amyloidogenic rat amylin peptide. Micron. 2012; 44:246-53. DOI: 10.1016/j.micron.2012.07.001. View

Zraika S, Hull R, Udayasankar J, Aston-Mourney K, Subramanian S, Kisilevsky R . Oxidative stress is induced by islet amyloid formation and time-dependently mediates amyloid-induced beta cell apoptosis. Diabetologia. 2009; 52(4):626-35. PMC: 2719780. DOI: 10.1007/s00125-008-1255-x. View

Abedini A, Schmidt A . Mechanisms of islet amyloidosis toxicity in type 2 diabetes. FEBS Lett. 2013; 587(8):1119-27. PMC: 4557799. DOI: 10.1016/j.febslet.2013.01.017. View

Manning M, Woody R . Theoretical CD studies of polypeptide helices: examination of important electronic and geometric factors. Biopolymers. 1991; 31(5):569-86. DOI: 10.1002/bip.360310511. View

10.

Marek P, Mukherjee S, Zanni M, Raleigh D . Residue-specific, real-time characterization of lag-phase species and fibril growth during amyloid formation: a combined fluorescence and IR study of p-cyanophenylalanine analogs of islet amyloid polypeptide. J Mol Biol. 2010; 400(4):878-88. PMC: 3061969. DOI: 10.1016/j.jmb.2010.05.041. View

11.

Wiltzius J, Sievers S, Sawaya M, Eisenberg D . Atomic structures of IAPP (amylin) fusions suggest a mechanism for fibrillation and the role of insulin in the process. Protein Sci. 2009; 18(7):1521-30. PMC: 2775219. DOI: 10.1002/pro.145. View

12.

Wang L, Middleton C, Singh S, Reddy A, Woys A, Strasfeld D . 2DIR spectroscopy of human amylin fibrils reflects stable β-sheet structure. J Am Chem Soc. 2011; 133(40):16062-71. PMC: 3196637. DOI: 10.1021/ja204035k. View

13.

Qiu W, Wallack M, Dean M, Liebson E, Mwamburi M, Zhu H . Association between amylin and amyloid-β peptides in plasma in the context of apolipoprotein E4 allele. PLoS One. 2014; 9(2):e88063. PMC: 3919737. DOI: 10.1371/journal.pone.0088063. View

14.

Potter K, Abedini A, Marek P, Klimek A, Butterworth S, Driscoll M . Islet amyloid deposition limits the viability of human islet grafts but not porcine islet grafts. Proc Natl Acad Sci U S A. 2010; 107(9):4305-10. PMC: 2840144. DOI: 10.1073/pnas.0909024107. View

15.

Middleton C, Woys A, Mukherjee S, Zanni M . Residue-specific structural kinetics of proteins through the union of isotope labeling, mid-IR pulse shaping, and coherent 2D IR spectroscopy. Methods. 2010; 52(1):12-22. PMC: 2933966. DOI: 10.1016/j.ymeth.2010.05.002. View

16.

Despa S, Sharma S, Harris T, Dong H, Li N, Chiamvimonvat N . Cardioprotection by controlling hyperamylinemia in a "humanized" diabetic rat model. J Am Heart Assoc. 2014; 3(4). PMC: 4310392. DOI: 10.1161/JAHA.114.001015. View

17.

Jha S, Snell J, Sheftic S, Patil S, Daniels S, Kolling F . pH dependence of amylin fibrillization. Biochemistry. 2014; 53(2):300-10. DOI: 10.1021/bi401164k. View

18.

Kim H, Cho M, Kumar A, Maier E, Siebenhaar C, Becker S . Structural properties of pore-forming oligomers of alpha-synuclein. J Am Chem Soc. 2009; 131(47):17482-9. DOI: 10.1021/ja9077599. View

19.

Westermark P, Engstrom U, Johnson K, Westermark G, Betsholtz C . Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. Proc Natl Acad Sci U S A. 1990; 87(13):5036-40. PMC: 54256. DOI: 10.1073/pnas.87.13.5036. View

20.

Magzoub M, Miranker A . Concentration-dependent transitions govern the subcellular localization of islet amyloid polypeptide. FASEB J. 2011; 26(3):1228-38. PMC: 3289502. DOI: 10.1096/fj.11-194613. View