Somatostatin binds to the human amyloid β peptide and favors the formation of distinct oligomers

  1. Hansen Wang
  2. Lisa D Muiznieks
  3. Punam Ghosh
  4. Declan Williams
  5. Michael Solarski
  6. Andrew Fang
  7. Alejandro Ruiz-Riquelme
  8. Régis Pomès
  9. Joel C Watts
  10. Avi Chakrabartty
  11. Holger Wille
  12. Simon Sharpe
  13. Gerold Schmitt-Ulms  Is a corresponding author
  1. University of Toronto, Canada
  2. The Hospital for Sick Children, Canada
  3. University of Alberta, Canada

Abstract

The amyloid β peptide (Aβ) is a key player in the etiology of Alzheimer disease (AD), yet a systematic investigation of its molecular interactions has not been reported. Here we identified by quantitative mass spectrometry proteins in human brain extract that bind to oligomeric Aβ1-42 (oAβ1-42) and/or monomeric Aβ1-42 (mAβ1-42) baits. Remarkably, the cyclic neuroendocrine peptide somatostatin-14 (SST14) was observed to be the most selectively enriched oAβ1-42 binder. The binding interface comprises a central tryptophan within SST14 and the N-terminus of Aβ1-42. The presence of SST14 inhibited Aβ aggregation and masked the ability of several antibodies to detect Aβ. Notably, Aβ1-42, but not Aβ1-40, formed in the presence of SST14 oligomeric assemblies of 50 to 60 kDa that were visualized by gel electrophoresis, nanoparticle tracking analysis and electron microscopy. These findings may be relevant for Aβ-directed diagnostics and may signify a role of SST14 in the etiology of AD.

Data availability

The following data sets were generated

Article and author information

Author details

  1. Hansen Wang

    Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
    Competing interests
    Hansen Wang, Holds provisionary US patent on amyloid-beta binding polypeptides based on the results of this study (filing number 62/451,309)..
  2. Lisa D Muiznieks

    Molecular Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    No competing interests declared.
  3. Punam Ghosh

    Department of Medical Biophysics, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  4. Declan Williams

    Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  5. Michael Solarski

    Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  6. Andrew Fang

    Department of Biochemistry, University of Alberta, Edmonton, Canada
    Competing interests
    No competing interests declared.
  7. Alejandro Ruiz-Riquelme

    Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6581-7132
  8. Régis Pomès

    Molecular Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3068-9833
  9. Joel C Watts

    Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  10. Avi Chakrabartty

    Department of Medical Biophysics, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  11. Holger Wille

    Department of Biochemistry, University of Alberta, Edmonton, Canada
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5102-8706
  12. Simon Sharpe

    Molecular Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    No competing interests declared.
  13. Gerold Schmitt-Ulms

    Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
    For correspondence
    g.schmittulms@utoronto.ca
    Competing interests
    Gerold Schmitt-Ulms, Holds provisionary US patent on amyloid-beta binding polypeptides based on the results of this study (filing number 62/451,309).
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6962-0919

Funding

Canadian Institutes of Health Research

  • Gerold Schmitt-Ulms

Ontario Centres for Excellence

  • Simon Sharpe
  • Gerold Schmitt-Ulms

Alberta Innovates Bio Solutions (201600028)

  • Holger Wille
  • Gerold Schmitt-Ulms

Heart and Stroke Foundation of Canada (G-15-0009148)

  • Simon Sharpe

Canada Foundation for Innovation

  • Gerold Schmitt-Ulms

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: The work was performed in strict accordance with University of Toronto animal care and biosafety recommendations. All mice were handled according to procedures approved (AUP4183.3) by the animal care committee at University Health Network overseeing work at the Krembil Discovery Centre (Toronto). The handling of samples and reagents followed biosafety procedures approved (208-S06-2) by the University of Toronto Biosafety Program.

Reviewing Editor

  1. Randy Schekman, Howard Hughes Medical Institute, University of California, Berkeley, United States

Publication history

  1. Received: November 18, 2016
  2. Accepted: June 14, 2017
  3. Accepted Manuscript published: June 26, 2017 (version 1)
  4. Version of Record published: July 11, 2017 (version 2)

Copyright

© 2017, Wang 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.

Metrics

  • 2,437
    Page views
  • 514
    Downloads
  • 24
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Hansen Wang
  2. Lisa D Muiznieks
  3. Punam Ghosh
  4. Declan Williams
  5. Michael Solarski
  6. Andrew Fang
  7. Alejandro Ruiz-Riquelme
  8. Régis Pomès
  9. Joel C Watts
  10. Avi Chakrabartty
  11. Holger Wille
  12. Simon Sharpe
  13. Gerold Schmitt-Ulms
(2017)
Somatostatin binds to the human amyloid β peptide and favors the formation of distinct oligomers
eLife 6:e28401.
https://doi.org/10.7554/eLife.28401

Further reading

    1. Biochemistry and Chemical Biology
    2. Microbiology and Infectious Disease
    Abhinay Ramaprasad, Paul-Christian Burda ... Michael J Blackman
    Research Article Updated

    The malaria parasite Plasmodium falciparum synthesizes significant amounts of phospholipids to meet the demands of replication within red blood cells. De novo phosphatidylcholine (PC) biosynthesis via the Kennedy pathway is essential, requiring choline that is primarily sourced from host serum lysophosphatidylcholine (lysoPC). LysoPC also acts as an environmental sensor to regulate parasite sexual differentiation. Despite these critical roles for host lysoPC, the enzyme(s) involved in its breakdown to free choline for PC synthesis are unknown. Here, we show that a parasite glycerophosphodiesterase (PfGDPD) is indispensable for blood stage parasite proliferation. Exogenous choline rescues growth of PfGDPD-null parasites, directly linking PfGDPD function to choline incorporation. Genetic ablation of PfGDPD reduces choline uptake from lysoPC, resulting in depletion of several PC species in the parasite, whilst purified PfGDPD releases choline from glycerophosphocholine in vitro. Our results identify PfGDPD as a choline-releasing glycerophosphodiesterase that mediates a critical step in PC biosynthesis and parasite survival.

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Jiemin Shen, Azaan Saalim Wilbon ... Yaping Pan
    Research Article Updated

    Ferroportin (Fpn) is a transporter that releases ferrous ion (Fe2+) from cells and is important for homeostasis of iron in circulation. Export of one Fe2+ by Fpn is coupled to import of two H+ to maintain charge balance. Here, we show that human Fpn (HsFpn) binds to and mediates Ca2+ transport. We determine the structure of Ca2+-bound HsFpn and identify a single Ca2+ binding site distinct from the Fe2+ binding sites. Further studies validate the Ca2+ binding site and show that Ca2+ transport is not coupled to transport of another ion. In addition, Ca2+ transport is significantly inhibited in the presence of Fe2+ but not vice versa. Function of Fpn as a Ca2+ uniporter may allow regulation of iron homeostasis by Ca2+.