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Secondary nucleation of monomers on fibril surface dominates α-synuclein aggregation and provides autocatalytic amyloid amplification

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 (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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organization
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Contribution to journal
publication status
published
subject
in
Quarterly Reviews of Biophysics
volume
50
publisher
Cambridge University Press
external identifiers
  • scopus:85027420278
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
2019-03-17 05:08:32
@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>},
  articleno    = {e6},
  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},
  volume       = {50},
  year         = {2017},
}