Single residue modulators of amyloid formation in the N-terminal P1-region of α-synuclein

Sabine M. Ulamec, Roberto Maya-Martinez, Emily J. Byrd, Katherine M. Dewison, Yong Xu, Leon F. Willis, Frank Sobott, George R. Heath, Patricija Oosten Hawle, Vladimir L. Buchman, Sheena E. Radford () and David J. Brockwell ()
Additional contact information
Sabine M. Ulamec: University of Leeds
Roberto Maya-Martinez: University of Leeds
Emily J. Byrd: University of Leeds
Katherine M. Dewison: University of Leeds
Yong Xu: University of Leeds
Leon F. Willis: University of Leeds
Frank Sobott: University of Leeds
George R. Heath: University of Leeds
Patricija Oosten Hawle: University of Leeds
Vladimir L. Buchman: Cardiff University
Sheena E. Radford: University of Leeds
David J. Brockwell: University of Leeds

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Alpha-synuclein (αSyn) is a protein involved in neurodegenerative disorders including Parkinson’s disease. Amyloid formation of αSyn can be modulated by the ‘P1 region’ (residues 36-42). Here, mutational studies of P1 reveal that Y39A and S42A extend the lag-phase of αSyn amyloid formation in vitro and rescue amyloid-associated cytotoxicity in C. elegans. Additionally, L38I αSyn forms amyloid fibrils more rapidly than WT, L38A has no effect, but L38M does not form amyloid fibrils in vitro and protects from proteotoxicity. Swapping the sequence of the two residues that differ in the P1 region of the paralogue γSyn to those of αSyn did not enhance fibril formation for γSyn. Peptide binding experiments using NMR showed that P1 synergises with residues in the NAC and C-terminal regions to initiate aggregation. The remarkable specificity of the interactions that control αSyn amyloid formation, identifies this region as a potential target for therapeutics, despite their weak and transient nature.

Date: 2022
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DOI: 10.1038/s41467-022-32687-1

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