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

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, Sarah Threlfell, Bradley Roberts, Thomas Schrader, Frank-Gerrit Klärner, Stephanie Cragg, Benjamin Dehay, Gal Bitan, Carlos Matute, Erwan Bezard and Richard Wade-Martins ()
Additional contact information
Nora Bengoa-Vergniory: Oxford University
Emilie Faggiani: Univ. de Bordeaux
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
Gal Bitan: University of California, Los Angeles
Carlos Matute: Universidad del País Vasco (UPV/EHU)
Erwan Bezard: Univ. de Bordeaux
Richard Wade-Martins: Oxford University

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18689-x

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