Self-replication of Aβ42 aggregates occurs on small and isolated fibril sites
(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
- Curk, Samo ; Krausser, Johannes ; Meisl, Georg ; Frenkel, Daan ; Linse, Sara LU ; Michaels, Thomas C.T. ; Knowles, Tuomas P.J. and Šarić, Anđela
- organization
- publishing date
- 2024-02-13
- 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}}, }