The C-terminal tail of α-synuclein protects against aggregate replication but is critical for oligomerization.
Authors
Farzadfard, Azad
Pedersen, Jannik Nedergaard
Somavarapu, Arun Kumar
Alam, Parvez
Publication Date
2022-02-10Journal Title
Commun Biol
ISSN
2399-3642
Publisher
Springer Science and Business Media LLC
Volume
5
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
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Farzadfard, A., Pedersen, J. N., Meisl, G., Somavarapu, A. K., Alam, P., Goksøyr, L., Nielsen, M. A., et al. (2022). The C-terminal tail of α-synuclein protects against aggregate replication but is critical for oligomerization.. Commun Biol, 5 (1) https://doi.org/10.1038/s42003-022-03059-8
Abstract
Aggregation of the 140-residue protein α-synuclein (αSN) is a key factor in the etiology of Parkinson's disease. Although the intensely anionic C-terminal domain (CTD) of αSN does not form part of the amyloid core region or affect membrane binding ability, truncation or reduction of charges in the CTD promotes fibrillation through as yet unknown mechanisms. Here, we study stepwise truncated CTDs and identify a threshold region around residue 121; constructs shorter than this dramatically increase their fibrillation tendency. Remarkably, these effects persist even when as little as 10% of the truncated variant is mixed with the full-length protein. Increased fibrillation can be explained by a substantial increase in self-replication, most likely via fragmentation. Paradoxically, truncation also suppresses toxic oligomer formation, and oligomers that can be formed by chemical modification show reduced membrane affinity and cytotoxicity. These remarkable changes correlate to the loss of negative electrostatic potential in the CTD and highlight a double-edged electrostatic safety guard.
Keywords
Article, /631/57, /631/337, /82/16, /82/29, /82/80, /82/83, /101/28, article
Identifiers
s42003-022-03059-8, 3059
External DOI: https://doi.org/10.1038/s42003-022-03059-8
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333848
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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