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Eye lens crystallin proteins inhibit the autocatalytic amyloid amplification nature of mature α-synuclein fibrils

Gaspar, Ricardo LU ; Garting, Tommy LU and Stradner, Anna LU (2020) In PLoS ONE 15(6).
Abstract

Parkinson´s disease is characterized by the accumulation of proteinaceous aggregates in Lewy bodies and Lewy Neurites. The main component found in such aggregates is α-synuclein. Here, we investigate how bovine eye lens crystallin proteins influence the aggregation kinetics of α-synuclein at mildly acidic pH (5.5) where the underlying aggregation mechanism of this protein is dominated by secondary nucleation of monomers on fibril surface providing an autocatalytic amyloid amplification process. Bovine α-, βH- and γB-crystallins were found to display chaperone-like activity inhibiting α-synuclein aggregation. This effect was shown to be time-dependent, with early additions of α-crystallin capable of retarding and even inhibiting... (More)

Parkinson´s disease is characterized by the accumulation of proteinaceous aggregates in Lewy bodies and Lewy Neurites. The main component found in such aggregates is α-synuclein. Here, we investigate how bovine eye lens crystallin proteins influence the aggregation kinetics of α-synuclein at mildly acidic pH (5.5) where the underlying aggregation mechanism of this protein is dominated by secondary nucleation of monomers on fibril surface providing an autocatalytic amyloid amplification process. Bovine α-, βH- and γB-crystallins were found to display chaperone-like activity inhibiting α-synuclein aggregation. This effect was shown to be time-dependent, with early additions of α-crystallin capable of retarding and even inhibiting aggregation during the time frame of the experiment. The inhibitory nature of crystallins was further investigated using trap and seed kinetic experiments. We propose crystallins interact with mature α-synuclein fibrils, possibly binding along the surfaces and at fibril free ends, inhibiting both elongation and monomer-dependent secondary nucleation processes in a mechanism that may be generic to some chaperones that prevent the onset of protein misfolding related pathologies.

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publication status
published
subject
in
PLoS ONE
volume
15
issue
6
article number
e0235198
publisher
Public Library of Science
external identifiers
  • pmid:32598365
  • scopus:85087325011
ISSN
1932-6203
DOI
10.1371/journal.pone.0235198
language
English
LU publication?
yes
id
9e4de176-8537-44c3-a304-b07ca4843827
date added to LUP
2020-07-17 09:51:56
date last changed
2020-07-18 03:00:01
@article{9e4de176-8537-44c3-a304-b07ca4843827,
  abstract     = {<p>Parkinson´s disease is characterized by the accumulation of proteinaceous aggregates in Lewy bodies and Lewy Neurites. The main component found in such aggregates is α-synuclein. Here, we investigate how bovine eye lens crystallin proteins influence the aggregation kinetics of α-synuclein at mildly acidic pH (5.5) where the underlying aggregation mechanism of this protein is dominated by secondary nucleation of monomers on fibril surface providing an autocatalytic amyloid amplification process. Bovine α-, βH- and γB-crystallins were found to display chaperone-like activity inhibiting α-synuclein aggregation. This effect was shown to be time-dependent, with early additions of α-crystallin capable of retarding and even inhibiting aggregation during the time frame of the experiment. The inhibitory nature of crystallins was further investigated using trap and seed kinetic experiments. We propose crystallins interact with mature α-synuclein fibrils, possibly binding along the surfaces and at fibril free ends, inhibiting both elongation and monomer-dependent secondary nucleation processes in a mechanism that may be generic to some chaperones that prevent the onset of protein misfolding related pathologies.</p>},
  author       = {Gaspar, Ricardo and Garting, Tommy and Stradner, Anna},
  issn         = {1932-6203},
  language     = {eng},
  number       = {6},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {Eye lens crystallin proteins inhibit the autocatalytic amyloid amplification nature of mature α-synuclein fibrils},
  url          = {http://dx.doi.org/10.1371/journal.pone.0235198},
  doi          = {10.1371/journal.pone.0235198},
  volume       = {15},
  year         = {2020},
}