Monomeric and fibrillar α-synuclein exert opposite effects on the catalytic cycle that promotes the proliferation of Aβ42 aggregates
(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
- Chia, Sean ; Flagmeier, Patrick ; Habchi, Johnny ; Lattanzi, Veronica LU ; Linse, Sara LU ; Dobson, Christopher M ; Knowles, Tuomas P J and Vendruscolo, Michele
- organization
- publishing date
- 2017-07-25
- 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 Academy of Sciences
- external identifiers
-
- pmid:28698377
- wos:000406189900072
- scopus:85025682103
- 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
- 2025-03-03 21:58:22
@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}},
keywords = {{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 Academy of 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}},
doi = {{10.1073/pnas.1700239114}},
volume = {{114}},
year = {{2017}},
}