Secondary nucleation of monomers on fibril surface dominates α-synuclein aggregation and provides autocatalytic amyloid amplification
(2017) In Quarterly Reviews of Biophysics 50.- Abstract
Parkinson's disease (PD) is characterized by proteinaceous aggregates named Lewy Bodies and Lewy Neurites containing α-synuclein fibrils. The underlying aggregation mechanism of this protein is dominated by a secondary process at mildly acidic pH, as in endosomes and other organelles. This effect manifests as a strong acceleration of the aggregation in the presence of seeds and a weak dependence of the aggregation rate on monomer concentration. The molecular mechanism underlying this process could be nucleation of monomers on fibril surfaces or fibril fragmentation. Here, we aim to distinguish between these mechanisms. The nature of the secondary processes was investigated using differential sedimentation analysis, trap and seed... (More)
Parkinson's disease (PD) is characterized by proteinaceous aggregates named Lewy Bodies and Lewy Neurites containing α-synuclein fibrils. The underlying aggregation mechanism of this protein is dominated by a secondary process at mildly acidic pH, as in endosomes and other organelles. This effect manifests as a strong acceleration of the aggregation in the presence of seeds and a weak dependence of the aggregation rate on monomer concentration. The molecular mechanism underlying this process could be nucleation of monomers on fibril surfaces or fibril fragmentation. Here, we aim to distinguish between these mechanisms. The nature of the secondary processes was investigated using differential sedimentation analysis, trap and seed experiments, quartz crystal microbalance experiments and super-resolution microscopy. The results identify secondary nucleation of monomers on the fibril surface as the dominant secondary process leading to rapid generation of new aggregates, while no significant contribution from fragmentation was found. The newly generated oligomeric species quickly elongate to further serve as templates for secondary nucleation and this may have important implications in the spreading of PD.
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- author
- Gaspar, Ricardo LU ; Meisl, Georg ; Buell, Alexander K. ; Young, Laurence ; Kaminski, Clemens F. LU ; Knowles, Tuomas P.J. ; Sparr, Emma LU and Linse, Sara LU
- organization
- publishing date
- 2017-01-01
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Quarterly Reviews of Biophysics
- volume
- 50
- article number
- e6
- publisher
- Cambridge University Press
- external identifiers
-
- scopus:85027420278
- pmid:29233218
- ISSN
- 0033-5835
- DOI
- 10.1017/S0033583516000172
- language
- English
- LU publication?
- yes
- id
- 74c6a44d-c3f2-4aa7-9038-1aaaabe84686
- date added to LUP
- 2018-09-24 15:09:06
- date last changed
- 2024-04-30 13:16:00
@article{74c6a44d-c3f2-4aa7-9038-1aaaabe84686,
abstract = {{<p>Parkinson's disease (PD) is characterized by proteinaceous aggregates named Lewy Bodies and Lewy Neurites containing α-synuclein fibrils. The underlying aggregation mechanism of this protein is dominated by a secondary process at mildly acidic pH, as in endosomes and other organelles. This effect manifests as a strong acceleration of the aggregation in the presence of seeds and a weak dependence of the aggregation rate on monomer concentration. The molecular mechanism underlying this process could be nucleation of monomers on fibril surfaces or fibril fragmentation. Here, we aim to distinguish between these mechanisms. The nature of the secondary processes was investigated using differential sedimentation analysis, trap and seed experiments, quartz crystal microbalance experiments and super-resolution microscopy. The results identify secondary nucleation of monomers on the fibril surface as the dominant secondary process leading to rapid generation of new aggregates, while no significant contribution from fragmentation was found. The newly generated oligomeric species quickly elongate to further serve as templates for secondary nucleation and this may have important implications in the spreading of PD.</p>}},
author = {{Gaspar, Ricardo and Meisl, Georg and Buell, Alexander K. and Young, Laurence and Kaminski, Clemens F. and Knowles, Tuomas P.J. and Sparr, Emma and Linse, Sara}},
issn = {{0033-5835}},
language = {{eng}},
month = {{01}},
publisher = {{Cambridge University Press}},
series = {{Quarterly Reviews of Biophysics}},
title = {{Secondary nucleation of monomers on fibril surface dominates α-synuclein aggregation and provides autocatalytic amyloid amplification}},
url = {{http://dx.doi.org/10.1017/S0033583516000172}},
doi = {{10.1017/S0033583516000172}},
volume = {{50}},
year = {{2017}},
}