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

Author

Listed:
  • 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
    Belgorod State National Research University)

  • Sheena E. Radford

    (University of Leeds)

  • David J. Brockwell

    (University of Leeds)

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.

Suggested Citation

  • 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. R, 2022. "Single residue modulators of amyloid formation in the N-terminal P1-region of α-synuclein," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32687-1
    DOI: 10.1038/s41467-022-32687-1
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