The properties of α-synuclein secondary nuclei are dominated by the solution conditions rather than the seed fibril strain
(2020) In ACS Chemical Neuroscience 11(6). p.909-918- Abstract
Amyloid fibrils of α-synuclein (α-syn) are a component of Lewy bodies, the characteristic hallmark of Parkinson's disease. Amyloid fibrils arise through primary nucleation from monomers, which in the case of α-syn is often heterogeneous, followed by the growth of the nuclei by monomer addition. Secondary nucleation corresponds to the formation of new fibrils facilitated by pre-existing fibrils. While it is well-established that the newly added monomer in fibril elongation adopts the conformation of the monomers in the seed ("templating"), it is unclear whether fibrils formed through secondary nucleation of monomers on the surface of seed fibrils copy the structure of the "parent" fibril. Here we show by biochemical and microscopical... (More)
Amyloid fibrils of α-synuclein (α-syn) are a component of Lewy bodies, the characteristic hallmark of Parkinson's disease. Amyloid fibrils arise through primary nucleation from monomers, which in the case of α-syn is often heterogeneous, followed by the growth of the nuclei by monomer addition. Secondary nucleation corresponds to the formation of new fibrils facilitated by pre-existing fibrils. While it is well-established that the newly added monomer in fibril elongation adopts the conformation of the monomers in the seed ("templating"), it is unclear whether fibrils formed through secondary nucleation of monomers on the surface of seed fibrils copy the structure of the "parent" fibril. Here we show by biochemical and microscopical methods that the secondary nucleation of α-syn, enabled at mildly acidic pH, leads to fibrils that structurally resemble more closely those formed de novo under the same conditions, rather than the seeds if these are formed under different solution condition. This result has important implications for the mechanistic understanding of the secondary nucleation of amyloid fibrils and its role in the propagation of aggregate pathology in protein misfolding diseases.
(Less)
- author
- Peduzzo, Alessia ; Linse, Sara LU and Buell, Alexander K.
- organization
- publishing date
- 2020-03-18
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- α-Synuclein, amyloid, Parkinson’s disease, secondary nucleation, fibril strain, propagation
- in
- ACS Chemical Neuroscience
- volume
- 11
- issue
- 6
- pages
- 10 pages
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- pmid:32069013
- scopus:85080880425
- ISSN
- 1948-7193
- DOI
- 10.1021/acschemneuro.9b00594
- language
- English
- LU publication?
- yes
- id
- 88b4e243-6ce5-4e48-ba7d-3ea556627429
- date added to LUP
- 2020-03-24 14:57:11
- date last changed
- 2024-03-04 15:02:15
@article{88b4e243-6ce5-4e48-ba7d-3ea556627429,
abstract = {{<p>Amyloid fibrils of α-synuclein (α-syn) are a component of Lewy bodies, the characteristic hallmark of Parkinson's disease. Amyloid fibrils arise through primary nucleation from monomers, which in the case of α-syn is often heterogeneous, followed by the growth of the nuclei by monomer addition. Secondary nucleation corresponds to the formation of new fibrils facilitated by pre-existing fibrils. While it is well-established that the newly added monomer in fibril elongation adopts the conformation of the monomers in the seed ("templating"), it is unclear whether fibrils formed through secondary nucleation of monomers on the surface of seed fibrils copy the structure of the "parent" fibril. Here we show by biochemical and microscopical methods that the secondary nucleation of α-syn, enabled at mildly acidic pH, leads to fibrils that structurally resemble more closely those formed de novo under the same conditions, rather than the seeds if these are formed under different solution condition. This result has important implications for the mechanistic understanding of the secondary nucleation of amyloid fibrils and its role in the propagation of aggregate pathology in protein misfolding diseases.</p>}},
author = {{Peduzzo, Alessia and Linse, Sara and Buell, Alexander K.}},
issn = {{1948-7193}},
keywords = {{α-Synuclein; amyloid; Parkinson’s disease; secondary nucleation; fibril strain; propagation}},
language = {{eng}},
month = {{03}},
number = {{6}},
pages = {{909--918}},
publisher = {{The American Chemical Society (ACS)}},
series = {{ACS Chemical Neuroscience}},
title = {{The properties of α-synuclein secondary nuclei are dominated by the solution conditions rather than the seed fibril strain}},
url = {{http://dx.doi.org/10.1021/acschemneuro.9b00594}},
doi = {{10.1021/acschemneuro.9b00594}},
volume = {{11}},
year = {{2020}},
}