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Solution conditions determine the relative importance of nucleation and growth processes in alpha-synuclein aggregation

Buell, Alexander K.; Galvagnion, Celine; Gaspar, Ricardo LU ; Sparr, Emma LU ; Vendruscolo, Michele; Knowles, Tuomas P. J.; Linse, Sara LU and Dobson, Christopher M. (2014) In Proceedings of the National Academy of Sciences 111(21). p.7671-7676
Abstract
The formation of amyloid fibrils by the intrinsically disordered protein alpha-synuclein is a hallmark of Parkinson disease. To characterize the microscopic steps in the mechanism of aggregation of this protein we have used in vitro aggregation assays in the presence of preformed seed fibrils to determine the molecular rate constant of fibril elongation under a range of different conditions. We show that alpha-synuclein amyloid fibrils grow by monomer and not oligomer addition and are subject to higher-order assembly processes that decrease their capacity to grow. We also find that at neutral pH under quiescent conditions homogeneous primary nucleation and secondary processes, such as fragmentation and surface-assisted nucleation, which... (More)
The formation of amyloid fibrils by the intrinsically disordered protein alpha-synuclein is a hallmark of Parkinson disease. To characterize the microscopic steps in the mechanism of aggregation of this protein we have used in vitro aggregation assays in the presence of preformed seed fibrils to determine the molecular rate constant of fibril elongation under a range of different conditions. We show that alpha-synuclein amyloid fibrils grow by monomer and not oligomer addition and are subject to higher-order assembly processes that decrease their capacity to grow. We also find that at neutral pH under quiescent conditions homogeneous primary nucleation and secondary processes, such as fragmentation and surface-assisted nucleation, which can lead to proliferation of the total number of aggregates, are undetectable. At pH values below 6, however, the rate of secondary nucleation increases dramatically, leading to a completely different balance between the nucleation and growth of aggregates. Thus, at mildly acidic pH values, such as those, for example, that are present in some intracellular locations, including endosomes and lysosomes, multiplication of aggregates is much faster than at normal physiological pH values, largely as a consequence of much more rapid secondary nucleation. These findings provide new insights into possible mechanisms of alpha-synuclein aggregation and aggregate spreading in the context of Parkinson disease. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
seeding, prion-like behavior, neurodegenerative disease, kinetic, analysis, electrostatic interactions
in
Proceedings of the National Academy of Sciences
volume
111
issue
21
pages
7671 - 7676
publisher
National Acad Sciences
external identifiers
  • wos:000336411300045
  • scopus:84901660540
ISSN
1091-6490
DOI
10.1073/pnas.1315346111
language
English
LU publication?
yes
id
dfc4d6fe-b818-4502-944f-fbd5ecc06c4b (old id 4559065)
date added to LUP
2014-07-17 14:23:13
date last changed
2017-11-12 03:06:46
@article{dfc4d6fe-b818-4502-944f-fbd5ecc06c4b,
  abstract     = {The formation of amyloid fibrils by the intrinsically disordered protein alpha-synuclein is a hallmark of Parkinson disease. To characterize the microscopic steps in the mechanism of aggregation of this protein we have used in vitro aggregation assays in the presence of preformed seed fibrils to determine the molecular rate constant of fibril elongation under a range of different conditions. We show that alpha-synuclein amyloid fibrils grow by monomer and not oligomer addition and are subject to higher-order assembly processes that decrease their capacity to grow. We also find that at neutral pH under quiescent conditions homogeneous primary nucleation and secondary processes, such as fragmentation and surface-assisted nucleation, which can lead to proliferation of the total number of aggregates, are undetectable. At pH values below 6, however, the rate of secondary nucleation increases dramatically, leading to a completely different balance between the nucleation and growth of aggregates. Thus, at mildly acidic pH values, such as those, for example, that are present in some intracellular locations, including endosomes and lysosomes, multiplication of aggregates is much faster than at normal physiological pH values, largely as a consequence of much more rapid secondary nucleation. These findings provide new insights into possible mechanisms of alpha-synuclein aggregation and aggregate spreading in the context of Parkinson disease.},
  author       = {Buell, Alexander K. and Galvagnion, Celine and Gaspar, Ricardo and Sparr, Emma and Vendruscolo, Michele and Knowles, Tuomas P. J. and Linse, Sara and Dobson, Christopher M.},
  issn         = {1091-6490},
  keyword      = {seeding,prion-like behavior,neurodegenerative disease,kinetic,analysis,electrostatic interactions},
  language     = {eng},
  number       = {21},
  pages        = {7671--7676},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Solution conditions determine the relative importance of nucleation and growth processes in alpha-synuclein aggregation},
  url          = {http://dx.doi.org/10.1073/pnas.1315346111},
  volume       = {111},
  year         = {2014},
}