Solution conditions determine the relative importance of nucleation and growth processes in alpha-synuclein aggregation
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4559065
- author
- Buell, Alexander K. ; Galvagnion, Celine ; Gaspar, Ricardo LU ; Sparr, Emma LU ; Vendruscolo, Michele ; Knowles, Tuomas P. J. ; Linse, Sara LU and Dobson, Christopher M.
- organization
- publishing date
- 2014
- 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 Academy of 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
- 2016-04-01 10:20:44
- date last changed
- 2023-11-09 17:34:12
@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}},
keywords = {{seeding; prion-like behavior; neurodegenerative disease; kinetic; analysis; electrostatic interactions}},
language = {{eng}},
number = {{21}},
pages = {{7671--7676}},
publisher = {{National Academy of 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}},
doi = {{10.1073/pnas.1315346111}},
volume = {{111}},
year = {{2014}},
}