α-Synuclein oligomers form by secondary nucleation
(2024) In Nature Communications 15(1).- Abstract
Oligomeric species arising during
the aggregation of α-synuclein are implicated as a major source of
toxicity in Parkinson’s disease, and thus a major potential drug target.
However, both their mechanism of formation and role in aggregation are
largely unresolved. Here we show that, at physiological pH and in the
absence of lipid membranes, α-synuclein aggregates form by secondary
nucleation, rather than simple primary nucleation, and that this process
is enhanced by agitation. Moreover, using a combination of single
molecule and bulk level techniques, we identify secondary nucleation on
the surfaces of existing fibrils, rather than formation directly from
monomers, as the dominant... (More)Oligomeric species arising during
(Less)
the aggregation of α-synuclein are implicated as a major source of
toxicity in Parkinson’s disease, and thus a major potential drug target.
However, both their mechanism of formation and role in aggregation are
largely unresolved. Here we show that, at physiological pH and in the
absence of lipid membranes, α-synuclein aggregates form by secondary
nucleation, rather than simple primary nucleation, and that this process
is enhanced by agitation. Moreover, using a combination of single
molecule and bulk level techniques, we identify secondary nucleation on
the surfaces of existing fibrils, rather than formation directly from
monomers, as the dominant source of oligomers. Our results highlight
secondary nucleation as not only the key source of oligomers, but also
the main mechanism of aggregate formation, and show that these processes
take place under conditions which recapitulate the neutral pH and ionic
strength of the cytosol.
- author
- organization
- publishing date
- 2024-12
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nature Communications
- volume
- 15
- issue
- 1
- article number
- 7083
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:39153989
- scopus:85201412803
- ISSN
- 2041-1723
- DOI
- 10.1038/s41467-024-50692-4
- language
- English
- LU publication?
- yes
- id
- daa0776e-410e-48a3-a447-9a15a7e25da5
- date added to LUP
- 2024-10-30 11:55:12
- date last changed
- 2025-07-10 23:17:35
@article{daa0776e-410e-48a3-a447-9a15a7e25da5,
abstract = {{<p>Oligomeric species arising during <br>
the aggregation of α-synuclein are implicated as a major source of <br>
toxicity in Parkinson’s disease, and thus a major potential drug target.<br>
However, both their mechanism of formation and role in aggregation are <br>
largely unresolved. Here we show that, at physiological pH and in the <br>
absence of lipid membranes, α-synuclein aggregates form by secondary <br>
nucleation, rather than simple primary nucleation, and that this process<br>
is enhanced by agitation. Moreover, using a combination of single <br>
molecule and bulk level techniques, we identify secondary nucleation on <br>
the surfaces of existing fibrils, rather than formation directly from <br>
monomers, as the dominant source of oligomers. Our results highlight <br>
secondary nucleation as not only the key source of oligomers, but also <br>
the main mechanism of aggregate formation, and show that these processes<br>
take place under conditions which recapitulate the neutral pH and ionic<br>
strength of the cytosol. </p>}},
author = {{Xu, Catherine K. and Meisl, Georg and Andrzejewska, Ewa A. and Krainer, Georg and Dear, Alexander J. and Castellana-Cruz, Marta and Turi, Soma and Edu, Irina A. and Vivacqua, Giorgio and Jacquat, Raphaël P.B. and Arter, William E. and Spillantini, Maria Grazia and Vendruscolo, Michele and Linse, Sara and Knowles, Tuomas P.J.}},
issn = {{2041-1723}},
language = {{eng}},
number = {{1}},
publisher = {{Nature Publishing Group}},
series = {{Nature Communications}},
title = {{α-Synuclein oligomers form by secondary nucleation}},
url = {{http://dx.doi.org/10.1038/s41467-024-50692-4}},
doi = {{10.1038/s41467-024-50692-4}},
volume = {{15}},
year = {{2024}},
}