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Monomeric and fibrillar α-synuclein exert opposite effects on the catalytic cycle that promotes the proliferation of Aβ42 aggregates

Chia, Sean; Flagmeier, Patrick; Habchi, Johnny; Lattanzi, Veronica LU ; Linse, Sara LU ; Dobson, Christopher M; Knowles, Tuomas P J and Vendruscolo, Michele (2017) In Proceedings of the National Academy of Sciences of the United States of America 114(30). p.8005-8010
Abstract

The coaggregation of the amyloid-β peptide (Aβ) and α-synuclein is commonly observed in a range of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. The complex interplay between Aβ and α-synuclein has led to seemingly contradictory results on whether α-synuclein promotes or inhibits Aβ aggregation. Here, we show how these conflicts can be rationalized and resolved by demonstrating that different structural forms of α-synuclein exert different effects on Aβ aggregation. Our results demonstrate that whereas monomeric α-synuclein blocks the autocatalytic proliferation of Aβ42 (the 42-residue form of Aβ) fibrils, fibrillar α-synuclein catalyses the heterogeneous nucleation of Aβ42 aggregates. It is thus the... (More)

The coaggregation of the amyloid-β peptide (Aβ) and α-synuclein is commonly observed in a range of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. The complex interplay between Aβ and α-synuclein has led to seemingly contradictory results on whether α-synuclein promotes or inhibits Aβ aggregation. Here, we show how these conflicts can be rationalized and resolved by demonstrating that different structural forms of α-synuclein exert different effects on Aβ aggregation. Our results demonstrate that whereas monomeric α-synuclein blocks the autocatalytic proliferation of Aβ42 (the 42-residue form of Aβ) fibrils, fibrillar α-synuclein catalyses the heterogeneous nucleation of Aβ42 aggregates. It is thus the specific balance between the concentrations of monomeric and fibrillar α-synuclein that determines the outcome of the Aβ42 aggregation reaction.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer’s disease, Amyloid fibrils, Chemical kinetics, Dementia with Lewy bodies, Parkinson’s disease
in
Proceedings of the National Academy of Sciences of the United States of America
volume
114
issue
30
pages
6 pages
publisher
National Acad Sciences
external identifiers
  • scopus:85025682103
  • wos:000406189900072
ISSN
0027-8424
DOI
10.1073/pnas.1700239114
language
English
LU publication?
yes
id
f56713db-3628-4426-8907-a8882f3c73dc
date added to LUP
2017-08-02 07:37:28
date last changed
2017-09-18 11:40:42
@article{f56713db-3628-4426-8907-a8882f3c73dc,
  abstract     = {<p>The coaggregation of the amyloid-β peptide (Aβ) and α-synuclein is commonly observed in a range of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. The complex interplay between Aβ and α-synuclein has led to seemingly contradictory results on whether α-synuclein promotes or inhibits Aβ aggregation. Here, we show how these conflicts can be rationalized and resolved by demonstrating that different structural forms of α-synuclein exert different effects on Aβ aggregation. Our results demonstrate that whereas monomeric α-synuclein blocks the autocatalytic proliferation of Aβ42 (the 42-residue form of Aβ) fibrils, fibrillar α-synuclein catalyses the heterogeneous nucleation of Aβ42 aggregates. It is thus the specific balance between the concentrations of monomeric and fibrillar α-synuclein that determines the outcome of the Aβ42 aggregation reaction.</p>},
  author       = {Chia, Sean and Flagmeier, Patrick and Habchi, Johnny and Lattanzi, Veronica and Linse, Sara and Dobson, Christopher M and Knowles, Tuomas P J and Vendruscolo, Michele},
  issn         = {0027-8424},
  keyword      = {Alzheimer’s disease,Amyloid fibrils,Chemical kinetics,Dementia with Lewy bodies,Parkinson’s disease},
  language     = {eng},
  month        = {07},
  number       = {30},
  pages        = {8005--8010},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences of the United States of America},
  title        = {Monomeric and fibrillar α-synuclein exert opposite effects on the catalytic cycle that promotes the proliferation of Aβ42 aggregates},
  url          = {http://dx.doi.org/10.1073/pnas.1700239114},
  volume       = {114},
  year         = {2017},
}