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Secondary nucleation in amyloid formation

Törnquist, Mattias LU ; Michaels, Thomas C.T.; Sanagavarapu, Kalyani LU ; Yang, Xiaoting LU ; Meisl, Georg; Cohen, Samuel I.A.; Knowles, Tuomas P.J. and Linse, Sara LU (2018) In Chemical Communications 54(63). p.8667-8684
Abstract

Nucleation of new peptide and protein aggregates on the surfaces of amyloid fibrils of the same peptide or protein has emerged in the past two decades as a major pathway for both the generation of molecular species responsible for cellular toxicity and for the autocatalytic proliferation of peptide and protein aggregates. A key question in current research is the molecular mechanism and driving forces governing such processes, known as secondary nucleation. In this context, the analogies with other self-assembling systems for which monomer-dependent secondary nucleation has been studied for more than a century provide a valuable source of inspiration. Here, we present a short overview of this background and then review recent results... (More)

Nucleation of new peptide and protein aggregates on the surfaces of amyloid fibrils of the same peptide or protein has emerged in the past two decades as a major pathway for both the generation of molecular species responsible for cellular toxicity and for the autocatalytic proliferation of peptide and protein aggregates. A key question in current research is the molecular mechanism and driving forces governing such processes, known as secondary nucleation. In this context, the analogies with other self-assembling systems for which monomer-dependent secondary nucleation has been studied for more than a century provide a valuable source of inspiration. Here, we present a short overview of this background and then review recent results regarding secondary nucleation of amyloid-forming peptides and proteins, focusing in particular on the amyloid β peptide (Aβ) from Alzheimer's disease, with some examples regarding α-synuclein from Parkinson's disease. Monomer-dependent secondary nucleation of Aβ was discovered using a combination of kinetic experiments, global analysis, seeding experiments and selective isotope-enrichment, which pinpoint the monomer as the origin of new aggregates in a fibril-catalyzed reaction. Insights into driving forces are gained from variations of solution conditions, temperature and peptide sequence. Selective inhibition of secondary nucleation is explored as an effective means to limit oligomer production and toxicity. We also review experiments aimed at finding interaction partners of oligomers generated by secondary nucleation in an ongoing aggregation process. At the end of this feature article we bring forward outstanding questions and testable mechanistic hypotheses regarding monomer-dependent secondary nucleation in amyloid formation.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Chemical Communications
volume
54
issue
63
pages
18 pages
publisher
Royal Society of Chemistry
external identifiers
  • scopus:85050976389
ISSN
1359-7345
DOI
10.1039/c8cc02204f
language
English
LU publication?
yes
id
7b5eda73-eec7-44e3-bf9e-6b61b781cd7f
date added to LUP
2018-10-01 12:03:54
date last changed
2019-08-18 04:51:29
@article{7b5eda73-eec7-44e3-bf9e-6b61b781cd7f,
  abstract     = {<p>Nucleation of new peptide and protein aggregates on the surfaces of amyloid fibrils of the same peptide or protein has emerged in the past two decades as a major pathway for both the generation of molecular species responsible for cellular toxicity and for the autocatalytic proliferation of peptide and protein aggregates. A key question in current research is the molecular mechanism and driving forces governing such processes, known as secondary nucleation. In this context, the analogies with other self-assembling systems for which monomer-dependent secondary nucleation has been studied for more than a century provide a valuable source of inspiration. Here, we present a short overview of this background and then review recent results regarding secondary nucleation of amyloid-forming peptides and proteins, focusing in particular on the amyloid β peptide (Aβ) from Alzheimer's disease, with some examples regarding α-synuclein from Parkinson's disease. Monomer-dependent secondary nucleation of Aβ was discovered using a combination of kinetic experiments, global analysis, seeding experiments and selective isotope-enrichment, which pinpoint the monomer as the origin of new aggregates in a fibril-catalyzed reaction. Insights into driving forces are gained from variations of solution conditions, temperature and peptide sequence. Selective inhibition of secondary nucleation is explored as an effective means to limit oligomer production and toxicity. We also review experiments aimed at finding interaction partners of oligomers generated by secondary nucleation in an ongoing aggregation process. At the end of this feature article we bring forward outstanding questions and testable mechanistic hypotheses regarding monomer-dependent secondary nucleation in amyloid formation.</p>},
  author       = {Törnquist, Mattias and Michaels, Thomas C.T. and Sanagavarapu, Kalyani and Yang, Xiaoting and Meisl, Georg and Cohen, Samuel I.A. and Knowles, Tuomas P.J. and Linse, Sara},
  issn         = {1359-7345},
  language     = {eng},
  number       = {63},
  pages        = {8667--8684},
  publisher    = {Royal Society of Chemistry},
  series       = {Chemical Communications},
  title        = {Secondary nucleation in amyloid formation},
  url          = {http://dx.doi.org/10.1039/c8cc02204f},
  volume       = {54},
  year         = {2018},
}