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CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease

Author

Listed:
  • Nora Bengoa-Vergniory

    (Oxford University)

  • Emilie Faggiani

    (Univ. de Bordeaux
    CNRS, Institut des Maladies Neurodégénératives, UMR 5293)

  • Paula Ramos-Gonzalez

    (Universidad del País Vasco (UPV/EHU))

  • Ecem Kirkiz

    (Oxford University)

  • Natalie Connor-Robson

    (Oxford University)

  • Liam V. Brown

    (Oxford University)

  • Ibrar Siddique

    (University of California, Los Angeles)

  • Zizheng Li

    (University of California, Los Angeles)

  • Siv Vingill

    (Oxford University)

  • Milena Cioroch

    (Oxford University)

  • Fabio Cavaliere

    (Universidad del País Vasco (UPV/EHU))

  • Sarah Threlfell

    (Oxford University)

  • Bradley Roberts

    (Oxford University)

  • Thomas Schrader

    (University of Duisburg-Essen)

  • Frank-Gerrit Klärner

    (University of Duisburg-Essen)

  • Stephanie Cragg

    (Oxford University)

  • Benjamin Dehay

    (Univ. de Bordeaux
    CNRS, Institut des Maladies Neurodégénératives, UMR 5293)

  • Gal Bitan

    (University of California, Los Angeles)

  • Carlos Matute

    (Universidad del País Vasco (UPV/EHU))

  • Erwan Bezard

    (Univ. de Bordeaux
    CNRS, Institut des Maladies Neurodégénératives, UMR 5293)

  • Richard Wade-Martins

    (Oxford University)

Abstract

Parkinson’s disease (PD) affects millions of patients worldwide and is characterized by alpha-synuclein aggregation in dopamine neurons. Molecular tweezers have shown high potential as anti-aggregation agents targeting positively charged residues of proteins undergoing amyloidogenic processes. Here we report that the molecular tweezer CLR01 decreased aggregation and toxicity in induced pluripotent stem cell-derived dopaminergic cultures treated with PD brain protein extracts. In microfluidic devices CLR01 reduced alpha-synuclein aggregation in cell somas when axonal terminals were exposed to alpha-synuclein oligomers. We then tested CLR01 in vivo in a humanized alpha-synuclein overexpressing mouse model; mice treated at 12 months of age when motor defects are mild exhibited an improvement in motor defects and a decreased oligomeric alpha-synuclein burden. Finally, CLR01 reduced alpha-synuclein-associated pathology in mice injected with alpha-synuclein aggregates into the striatum or substantia nigra. Taken together, these results highlight CLR01 as a disease-modifying therapy for PD and support further clinical investigation.

Suggested Citation

  • Nora Bengoa-Vergniory & Emilie Faggiani & Paula Ramos-Gonzalez & Ecem Kirkiz & Natalie Connor-Robson & Liam V. Brown & Ibrar Siddique & Zizheng Li & Siv Vingill & Milena Cioroch & Fabio Cavaliere & Sa, 2020. "CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18689-x
    DOI: 10.1038/s41467-020-18689-x
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