1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics

  1. Andisheh Abedini
  2. Annette Plesner
  3. Ping Cao
  4. Zachary Ridgway
  5. Jinghua Zhang
  6. Ling-Hsien Tu
  7. Chris T Middleton
  8. Brian Chao
  9. Daniel Sartori
  10. Fanling Meng
  11. Hui Wang
  12. Amy G Wong
  13. Martin T Zanni
  14. C Bruce Verchere
  15. Daniel P Raleigh
  16. Ann Marie Schmidt  Is a corresponding author
  1. New York University School of Medicine, United States
  2. Novo Nordisk, Denmark
  3. Stony Brook University, United States
  4. PhaseTech Spectroscopy, Inc., United States
  5. University of Wisconsin-Madison, United States
  6. University of British Columbia, Canada
Research Article
  • Cited 38
  • Views 2,420
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Cite this article as: eLife 2016;5:e12977 doi: 10.7554/eLife.12977

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.

Article and author information

Author details

  1. Andisheh Abedini

    Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Annette Plesner

    Novo Nordisk, Bagsværd, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  3. Ping Cao

    Department of Chemistry, Stony Brook University, Stony Brook, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Zachary Ridgway

    Department of Chemistry, Stony Brook University, Stony Brook, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jinghua Zhang

    Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Ling-Hsien Tu

    Department of Chemistry, Stony Brook University, Stony Brook, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Chris T Middleton

    PhaseTech Spectroscopy, Inc., Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Brian Chao

    Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Daniel Sartori

    Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Fanling Meng

    Department of Chemistry, Stony Brook University, Stony Brook, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Hui Wang

    Department of Chemistry, Stony Brook University, Stony Brook, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Amy G Wong

    Department of Chemistry, Stony Brook University, Stony Brook, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Martin T Zanni

    Department of Chemistry, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. C Bruce Verchere

    Child & Family Research Institute and Department of Surgery and Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  15. Daniel P Raleigh

    Department of Chemistry, Stony Brook University, Stony Brook, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Ann Marie Schmidt

    Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, United States
    For correspondence
    annmarie.schmidt@nyumc.org
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All procedures were approved by the Institutional Animal Care and Use Committee of New York University Langone Medical Center (NYULMC) and conform to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH) (8th Edition, 2011, ISBN 10: 0-309-15400-6). The Animal Care and Use Program at NYULMC are in full compliance with NIH policy (NYULMC Compliance Number is A3435-01).

Reviewing Editor

  1. Jeffery W Kelly, The Scripps Research Institute, United States

Publication history

  1. Received: November 12, 2015
  2. Accepted: May 20, 2016
  3. Accepted Manuscript published: May 23, 2016 (version 1)
  4. Accepted Manuscript updated: June 1, 2016 (version 2)
  5. Version of Record published: July 11, 2016 (version 3)

Copyright

© 2016, Abedini et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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