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Foldamers reveal and validate therapeutic targets associated with toxic α-synuclein self-assembly

Author

Listed:
  • Jemil Ahmed

    (University of Denver
    University of Denver)

  • Tessa C. Fitch

    (University of Denver
    University of Denver)

  • Courtney M. Donnelly

    (University of Denver
    University of Denver)

  • Johnson A. Joseph

    (University of Denver
    University of Denver)

  • Tyler D. Ball

    (University of Denver
    University of Denver)

  • Mikaela M. Bassil

    (University of Denver
    University of Denver)

  • Ahyun Son

    (University of Denver
    University of Denver)

  • Chen Zhang

    (University of Denver)

  • Aurélie Ledreux

    (University of Denver)

  • Scott Horowitz

    (University of Denver
    University of Denver
    University of Denver)

  • Yan Qin

    (University of Denver)

  • Daniel Paredes

    (University of Denver)

  • Sunil Kumar

    (University of Denver
    University of Denver
    University of Denver)

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder for which there is no successful prevention or intervention. The pathological hallmark for PD involves the self-assembly of functional Alpha-Synuclein (αS) into non-functional amyloid structures. One of the potential therapeutic interventions against PD is the effective inhibition of αS aggregation. However, the bottleneck towards achieving this goal is the identification of αS domains/sequences that are essential for aggregation. Using a protein mimetic approach, we have identified αS sequences-based targets that are essential for aggregation and will have significant therapeutic implications. An extensive array of in vitro, ex vivo, and in vivo assays is utilized to validate αS sequences and their structural characteristics that are essential for aggregation and propagation of PD phenotypes. The study aids in developing significant mechanistic and therapeutic insights into various facets of αS aggregation, which will pave the way for effective treatments for PD.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29724-4
    DOI: 10.1038/s41467-022-29724-4
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    References listed on IDEAS

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    1. Luc Bousset & Laura Pieri & Gemma Ruiz-Arlandis & Julia Gath & Poul Henning Jensen & Birgit Habenstein & Karine Madiona & Vincent Olieric & Anja Böckmann & Beat H. Meier & Ronald Melki, 2013. "Structural and functional characterization of two alpha-synuclein strains," Nature Communications, Nature, vol. 4(1), pages 1-13, December.
    2. 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.
    3. Sunil Kumar & Melissa Birol & Diana E. Schlamadinger & Slawomir P. Wojcik & Elizabeth Rhoades & Andrew D. Miranker, 2016. "Foldamer-mediated manipulation of a pre-amyloid toxin," Nature Communications, Nature, vol. 7(1), pages 1-11, September.
    4. 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.
    5. Mohammad Shahnawaz & Abhisek Mukherjee & Sandra Pritzkow & Nicolas Mendez & Prakruti Rabadia & Xiangan Liu & Bo Hu & Ann Schmeichel & Wolfgang Singer & Gang Wu & Ah-Lim Tsai & Hamid Shirani & K. Peter, 2020. "Discriminating α-synuclein strains in Parkinson’s disease and multiple system atrophy," Nature, Nature, vol. 578(7794), pages 273-277, February.
    6. Giuliana Fusco & Alfonso De Simone & Tata Gopinath & Vitaly Vostrikov & Michele Vendruscolo & Christopher M. Dobson & Gianluigi Veglia, 2014. "Direct observation of the three regions in α-synuclein that determine its membrane-bound behaviour," Nature Communications, Nature, vol. 5(1), pages 1-8, September.
    7. Melissa Birol & Sunil Kumar & Elizabeth Rhoades & Andrew D. Miranker, 2018. "Conformational switching within dynamic oligomers underpins toxic gain-of-function by diabetes-associated amyloid," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    8. Taylor F. Minckley & Chen Zhang & Dylan H. Fudge & Anna M. Dischler & Kate D. LeJeune & Haoxing Xu & Yan Qin, 2019. "Sub-nanomolar sensitive GZnP3 reveals TRPML1-mediated neuronal Zn2+ signals," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
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    Cited by:

    1. Nicholas H. Stillman & Johnson A. Joseph & Jemil Ahmed & Charles Zuwu Baysah & Ryan A. Dohoney & Tyler D. Ball & Alexandra G. Thomas & Tessa C. Fitch & Courtney M. Donnelly & Sunil Kumar, 2024. "Protein mimetic 2D FAST rescues alpha synuclein aggregation mediated early and post disease Parkinson’s phenotypes," Nature Communications, Nature, vol. 15(1), pages 1-25, December.

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