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The properties of α-synuclein secondary nuclei are dominated by the solution conditions rather than the seed fibril strain

Peduzzo, Alessia ; Linse, Sara LU and Buell, Alexander K. (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.

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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
  • scopus:85080880425
  • pmid:32069013
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
2021-03-31 03:25:55
@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},
  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},
}