The C-terminal tail of α-synuclein protects against aggregate replication but is critical for oligomerization

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

The C-terminal tail of α-synuclein protects against aggregate replication but is critical for oligomerization. / Farzadfard, Azad; Pedersen, Jannik Nedergaard; Meisl, Georg; Somavarapu, Arun Kumar; Alam, Parvez; Goksøyr, Louise; Nielsen, Morten Agertoug; Sander, Adam Frederik; Knowles, Tuomas P.J.; Pedersen, Jan Skov; Otzen, Daniel Erik.

In: Communications Biology , Vol. 5, No. 1, 123, 2022.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Farzadfard, A, Pedersen, JN, Meisl, G, Somavarapu, AK, Alam, P, Goksøyr, L, Nielsen, MA, Sander, AF, Knowles, TPJ, Pedersen, JS & Otzen, DE 2022, 'The C-terminal tail of α-synuclein protects against aggregate replication but is critical for oligomerization', Communications Biology , vol. 5, no. 1, 123. https://doi.org/10.1038/s42003-022-03059-8

APA

Farzadfard, A., Pedersen, J. N., Meisl, G., Somavarapu, A. K., Alam, P., Goksøyr, L., Nielsen, M. A., Sander, A. F., Knowles, T. P. J., Pedersen, J. S., & Otzen, D. E. (2022). The C-terminal tail of α-synuclein protects against aggregate replication but is critical for oligomerization. Communications Biology , 5(1), [123]. https://doi.org/10.1038/s42003-022-03059-8

Vancouver

Farzadfard A, Pedersen JN, Meisl G, Somavarapu AK, Alam P, Goksøyr L et al. The C-terminal tail of α-synuclein protects against aggregate replication but is critical for oligomerization. Communications Biology . 2022;5(1). 123. https://doi.org/10.1038/s42003-022-03059-8

Author

Farzadfard, Azad ; Pedersen, Jannik Nedergaard ; Meisl, Georg ; Somavarapu, Arun Kumar ; Alam, Parvez ; Goksøyr, Louise ; Nielsen, Morten Agertoug ; Sander, Adam Frederik ; Knowles, Tuomas P.J. ; Pedersen, Jan Skov ; Otzen, Daniel Erik. / The C-terminal tail of α-synuclein protects against aggregate replication but is critical for oligomerization. In: Communications Biology . 2022 ; Vol. 5, No. 1.

Bibtex

@article{e6798f0b32294be18f144ce53aa8af6b,
title = "The C-terminal tail of α-synuclein protects against aggregate replication but is critical for oligomerization",
abstract = "Aggregation of the 140-residue protein α-synuclein (αSN) is a key factor in the etiology of Parkinson{\textquoteright}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.",
author = "Azad Farzadfard and Pedersen, {Jannik Nedergaard} and Georg Meisl and Somavarapu, {Arun Kumar} and Parvez Alam and Louise Goks{\o}yr and Nielsen, {Morten Agertoug} and Sander, {Adam Frederik} and Knowles, {Tuomas P.J.} and Pedersen, {Jan Skov} and Otzen, {Daniel Erik}",
note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
doi = "10.1038/s42003-022-03059-8",
language = "English",
volume = "5",
journal = "Communications Biology",
issn = "2399-3642",
publisher = "nature publishing group",
number = "1",

}

RIS

TY - JOUR

T1 - The C-terminal tail of α-synuclein protects against aggregate replication but is critical for oligomerization

AU - Farzadfard, Azad

AU - Pedersen, Jannik Nedergaard

AU - Meisl, Georg

AU - Somavarapu, Arun Kumar

AU - Alam, Parvez

AU - Goksøyr, Louise

AU - Nielsen, Morten Agertoug

AU - Sander, Adam Frederik

AU - Knowles, Tuomas P.J.

AU - Pedersen, Jan Skov

AU - Otzen, Daniel Erik

N1 - Publisher Copyright: © 2022, The Author(s).

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

U2 - 10.1038/s42003-022-03059-8

DO - 10.1038/s42003-022-03059-8

M3 - Journal article

C2 - 35145226

AN - SCOPUS:85124447913

VL - 5

JO - Communications Biology

JF - Communications Biology

SN - 2399-3642

IS - 1

M1 - 123

ER -

ID: 298634158