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Surface-Catalyzed Secondary Nucleation Dominates the Generation of Toxic IAPP Aggregates

Rodriguez Camargo, Diana C. ; Chia, Sean ; Menzies, Joseph ; Mannini, Benedetta ; Meisl, Georg ; Lundqvist, Martin LU ; Pohl, Christin LU ; Bernfur, Katja LU ; Lattanzi, Veronica LU and Habchi, Johnny , et al. (2021) In Frontiers in Molecular Biosciences 8.
Abstract

The aggregation of the human islet amyloid polypeptide (IAPP) is associated with diabetes type II. A quantitative understanding of this connection at the molecular level requires that the aggregation mechanism of IAPP is resolved in terms of the underlying microscopic steps. Here we have systematically studied recombinant IAPP, with amidated C-terminus in oxidised form with a disulphide bond between residues 3 and 7, using thioflavin T fluorescence to monitor the formation of amyloid fibrils as a function of time and IAPP concentration. We used global kinetic analyses to connect the macroscopic measurements of aggregation to the microscopic mechanisms, and show that the generation of new aggregates is dominated by the secondary... (More)

The aggregation of the human islet amyloid polypeptide (IAPP) is associated with diabetes type II. A quantitative understanding of this connection at the molecular level requires that the aggregation mechanism of IAPP is resolved in terms of the underlying microscopic steps. Here we have systematically studied recombinant IAPP, with amidated C-terminus in oxidised form with a disulphide bond between residues 3 and 7, using thioflavin T fluorescence to monitor the formation of amyloid fibrils as a function of time and IAPP concentration. We used global kinetic analyses to connect the macroscopic measurements of aggregation to the microscopic mechanisms, and show that the generation of new aggregates is dominated by the secondary nucleation of monomers on the fibril surface. We then exposed insulinoma cells to aliquots extracted from different time points of the aggregation process, finding the highest toxicity at the midpoint of the reaction, when the secondary nucleation rate reaches its maximum. These results identify IAPP oligomers as the most cytotoxic species generated during IAPP aggregation, and suggest that compounds that target secondary nucleation of IAPP could be most effective as therapeutic candidates for diabetes type II.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
amyloid formation, optical spectroscopy, peptide purification, reaction mechanism, self-assembly
in
Frontiers in Molecular Biosciences
volume
8
article number
757425
publisher
Frontiers Media S. A.
external identifiers
  • pmid:34790701
  • scopus:85119283839
ISSN
2296-889X
DOI
10.3389/fmolb.2021.757425
language
English
LU publication?
yes
additional info
Publisher Copyright: © Copyright © 2021 Rodriguez Camargo, Chia, Menzies, Mannini, Meisl, Lundqvist, Pohl, Bernfur, Lattanzi, Habchi, Cohen, Knowles, Vendruscolo and Linse.
id
d44844bf-59ce-460f-b9bb-3752c31616c2
date added to LUP
2021-12-20 16:42:48
date last changed
2024-04-20 18:03:26
@article{d44844bf-59ce-460f-b9bb-3752c31616c2,
  abstract     = {{<p>The aggregation of the human islet amyloid polypeptide (IAPP) is associated with diabetes type II. A quantitative understanding of this connection at the molecular level requires that the aggregation mechanism of IAPP is resolved in terms of the underlying microscopic steps. Here we have systematically studied recombinant IAPP, with amidated C-terminus in oxidised form with a disulphide bond between residues 3 and 7, using thioflavin T fluorescence to monitor the formation of amyloid fibrils as a function of time and IAPP concentration. We used global kinetic analyses to connect the macroscopic measurements of aggregation to the microscopic mechanisms, and show that the generation of new aggregates is dominated by the secondary nucleation of monomers on the fibril surface. We then exposed insulinoma cells to aliquots extracted from different time points of the aggregation process, finding the highest toxicity at the midpoint of the reaction, when the secondary nucleation rate reaches its maximum. These results identify IAPP oligomers as the most cytotoxic species generated during IAPP aggregation, and suggest that compounds that target secondary nucleation of IAPP could be most effective as therapeutic candidates for diabetes type II.</p>}},
  author       = {{Rodriguez Camargo, Diana C. and Chia, Sean and Menzies, Joseph and Mannini, Benedetta and Meisl, Georg and Lundqvist, Martin and Pohl, Christin and Bernfur, Katja and Lattanzi, Veronica and Habchi, Johnny and Cohen, Samuel I.A. and Knowles, Tuomas P.J. and Vendruscolo, Michele and Linse, Sara}},
  issn         = {{2296-889X}},
  keywords     = {{amyloid formation; optical spectroscopy; peptide purification; reaction mechanism; self-assembly}},
  language     = {{eng}},
  month        = {{11}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Molecular Biosciences}},
  title        = {{Surface-Catalyzed Secondary Nucleation Dominates the Generation of Toxic IAPP Aggregates}},
  url          = {{http://dx.doi.org/10.3389/fmolb.2021.757425}},
  doi          = {{10.3389/fmolb.2021.757425}},
  volume       = {{8}},
  year         = {{2021}},
}