IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-32687-1.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-32687-1
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-32687-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Jose A. Rodriguez & Magdalena I. Ivanova & Michael R. Sawaya & Duilio Cascio & Francis E. Reyes & Dan Shi & Smriti Sangwan & Elizabeth L. Guenther & Lisa M. Johnson & Meng Zhang & Lin Jiang & Mark A. , 2015. "Structure of the toxic core of α-synuclein from invisible crystals," Nature, Nature, vol. 525(7570), pages 486-490, September.
    2. Anne S. Wentink & Nadinath B. Nillegoda & Jennifer Feufel & Gabrielė Ubartaitė & Carolyn P. Schneider & Paolo De Los Rios & Janosch Hennig & Alessandro Barducci & Bernd Bukau, 2020. "Molecular dissection of amyloid disaggregation by human HSP70," Nature, Nature, vol. 587(7834), pages 483-488, November.
    3. Jessica S. Ebo & Janet C. Saunders & Paul W. A. Devine & Alice M. Gordon & Amy S. Warwick & Bob Schiffrin & Stacey E. Chin & Elizabeth England & James D. Button & Christopher Lloyd & Nicholas J. Bond , 2020. "An in vivo platform to select and evolve aggregation-resistant proteins," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    4. W. Peelaerts & L. Bousset & A. Van der Perren & A. Moskalyuk & R. Pulizzi & M. Giugliano & C. Van den Haute & R. Melki & V. Baekelandt, 2015. "α-Synuclein strains cause distinct synucleinopathies after local and systemic administration," Nature, Nature, vol. 522(7556), pages 340-344, June.
    5. Björn M. Burmann & Juan A. Gerez & Irena Matečko-Burmann & Silvia Campioni & Pratibha Kumari & Dhiman Ghosh & Adam Mazur & Emelie E. Aspholm & Darius Šulskis & Magdalena Wawrzyniuk & Thomas Bock & Ale, 2020. "Regulation of α-synuclein by chaperones in mammalian cells," Nature, Nature, vol. 577(7788), pages 127-132, January.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Jemil Ahmed & Tessa C. Fitch & Courtney M. Donnelly & Johnson A. Joseph & Tyler D. Ball & Mikaela M. Bassil & Ahyun Son & Chen Zhang & Aurélie Ledreux & Scott Horowitz & Yan Qin & Daniel Paredes & Sun, 2022. "Foldamers reveal and validate therapeutic targets associated with toxic α-synuclein self-assembly," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Itika Saha & Patricia Yuste-Checa & Miguel Silva Padilha & Qiang Guo & Roman Körner & Hauke Holthusen & Victoria A. Trinkaus & Irina Dudanova & Rubén Fernández-Busnadiego & Wolfgang Baumeister & David, 2023. "The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Matthias M. Schneider & Saurabh Gautam & Therese W. Herling & Ewa Andrzejewska & Georg Krainer & Alyssa M. Miller & Victoria A. Trinkaus & Quentin A. E. Peter & Francesco Simone Ruggeri & Michele Vend, 2021. "The Hsc70 disaggregation machinery removes monomer units directly from α-synuclein fibril ends," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    4. Norihito Uemura & Nicholas P. Marotta & Jahan Ara & Emily S. Meymand & Bin Zhang & Hiroshi Kameda & Masato Koike & Kelvin C. Luk & John Q. Trojanowski & Virginia M.-Y. Lee, 2023. "α-Synuclein aggregates amplified from patient-derived Lewy bodies recapitulate Lewy body diseases in mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. Ankan K. Bhadra & Michael J. Rau & Jil A. Daw & James A. J. Fitzpatrick & Conrad C. Weihl & Heather L. True, 2022. "Disease-associated mutations within the yeast DNAJB6 homolog Sis1 slow conformer-specific substrate processing and can be corrected by the modulation of nucleotide exchange factors," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    6. Ricarda Törner & Tatsiana Kupreichyk & Lothar Gremer & Elisa Colas Debled & Daphna Fenel & Sarah Schemmert & Pierre Gans & Dieter Willbold & Guy Schoehn & Wolfgang Hoyer & Jerome Boisbouvier, 2022. "Structural basis for the inhibition of IAPP fibril formation by the co-chaperonin prefoldin," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    7. Eduardo Pinho Melo & Tasuku Konno & Ilaria Farace & Mosab Ali Awadelkareem & Lise R. Skov & Fernando Teodoro & Teresa P. Sancho & Adrienne W. Paton & James C. Paton & Matthew Fares & Pedro M. R. Paulo, 2022. "Stress-induced protein disaggregation in the endoplasmic reticulum catalysed by BiP," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    8. Meital Abayev-Avraham & Yehuda Salzberg & Dar Gliksberg & Meital Oren-Suissa & Rina Rosenzweig, 2023. "DNAJB6 mutants display toxic gain of function through unregulated interaction with Hsp70 chaperones," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    9. Iosif Pediaditakis & Konstantia R. Kodella & Dimitris V. Manatakis & Christopher Y. Le & Chris D. Hinojosa & William Tien-Street & Elias S. Manolakos & Kostas Vekrellis & Geraldine A. Hamilton & Lorna, 2021. "Modeling alpha-synuclein pathology in a human brain-chip to assess blood-brain barrier disruption," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    10. Angelo Rosace & Anja Bennett & Marc Oeller & Mie M. Mortensen & Laila Sakhnini & Nikolai Lorenzen & Christian Poulsen & Pietro Sormanni, 2023. "Automated optimisation of solubility and conformational stability of antibodies and proteins," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    11. S. M. Ayala Mariscal & M. L. Pigazzini & Y. Richter & M. Özel & I. L. Grothaus & J. Protze & K. Ziege & M. Kulke & M. ElBediwi & J. V. Vermaas & L. Colombi Ciacchi & S. Köppen & F. Liu & J. Kirstein, 2022. "Identification of a HTT-specific binding motif in DNAJB1 essential for suppression and disaggregation of HTT," Nature Communications, Nature, vol. 13(1), pages 1-25, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32687-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.