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Self-replication of Aβ42 aggregates occurs on small and isolated fibril sites

Curk, Samo ; Krausser, Johannes ; Meisl, Georg ; Frenkel, Daan ; Linse, Sara LU ; Michaels, Thomas C.T. ; Knowles, Tuomas P.J. and Šarić, Anđela (2024) In Proceedings of the National Academy of Sciences of the United States of America 121(7). p.2220075121-2220075121
Abstract

Self-replication of amyloid fibrils via secondary nucleation is an intriguing physicochemical phenomenon in which existing fibrils catalyze the formation of their own copies. The molecular events behind this fibril surface-mediated process remain largely inaccessible to current structural and imaging techniques. Using statistical mechanics, computer modeling, and chemical kinetics, we show that the catalytic structure of the fibril surface can be inferred from the aggregation behavior in the presence and absence of a fibril-binding inhibitor. We apply our approach to the case of Alzheimer's A[Formula: see text] amyloid fibrils formed in the presence of proSP-C Brichos inhibitors. We find that self-replication of A[Formula: see text]... (More)

Self-replication of amyloid fibrils via secondary nucleation is an intriguing physicochemical phenomenon in which existing fibrils catalyze the formation of their own copies. The molecular events behind this fibril surface-mediated process remain largely inaccessible to current structural and imaging techniques. Using statistical mechanics, computer modeling, and chemical kinetics, we show that the catalytic structure of the fibril surface can be inferred from the aggregation behavior in the presence and absence of a fibril-binding inhibitor. We apply our approach to the case of Alzheimer's A[Formula: see text] amyloid fibrils formed in the presence of proSP-C Brichos inhibitors. We find that self-replication of A[Formula: see text] fibrils occurs on small catalytic sites on the fibril surface, which are far apart from each other, and each of which can be covered by a single Brichos inhibitor.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
amyloid aggregation, auto-catalysis, inhibition mechanism, secondary nucleation, self-replication
in
Proceedings of the National Academy of Sciences of the United States of America
volume
121
issue
7
pages
2220075121 - 2220075121
publisher
National Academy of Sciences
external identifiers
  • pmid:38335256
  • scopus:85184702735
ISSN
1091-6490
DOI
10.1073/pnas.2220075121
language
English
LU publication?
yes
id
eb012106-4bd9-435e-84e7-bffd78cd10d4
date added to LUP
2024-02-22 15:59:16
date last changed
2024-04-23 16:14:04
@article{eb012106-4bd9-435e-84e7-bffd78cd10d4,
  abstract     = {{<p>Self-replication of amyloid fibrils via secondary nucleation is an intriguing physicochemical phenomenon in which existing fibrils catalyze the formation of their own copies. The molecular events behind this fibril surface-mediated process remain largely inaccessible to current structural and imaging techniques. Using statistical mechanics, computer modeling, and chemical kinetics, we show that the catalytic structure of the fibril surface can be inferred from the aggregation behavior in the presence and absence of a fibril-binding inhibitor. We apply our approach to the case of Alzheimer's A[Formula: see text] amyloid fibrils formed in the presence of proSP-C Brichos inhibitors. We find that self-replication of A[Formula: see text] fibrils occurs on small catalytic sites on the fibril surface, which are far apart from each other, and each of which can be covered by a single Brichos inhibitor.</p>}},
  author       = {{Curk, Samo and Krausser, Johannes and Meisl, Georg and Frenkel, Daan and Linse, Sara and Michaels, Thomas C.T. and Knowles, Tuomas P.J. and Šarić, Anđela}},
  issn         = {{1091-6490}},
  keywords     = {{amyloid aggregation; auto-catalysis; inhibition mechanism; secondary nucleation; self-replication}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{7}},
  pages        = {{2220075121--2220075121}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{Self-replication of A<i>β</i><sub>42</sub> aggregates occurs on small and isolated fibril sites}},
  url          = {{http://dx.doi.org/10.1073/pnas.2220075121}},
  doi          = {{10.1073/pnas.2220075121}},
  volume       = {{121}},
  year         = {{2024}},
}