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

Bengoa-Vergniory, Nora, Faggiani, Emilie, Ramos-Gonzalez, Paula, Kirkiz, Ecem, Connor-Robson, Natalie ORCID:, Brown, Liam V., Siddique, Ibrar, Li, Zizheng, Vingill, Siv, Cioroch, Milena, Cavaliere, Fabio, Threlfell, Sarah, Roberts, Bradley, Schrader, Thomas, Klärner, Frank-Gerrit, Cragg, Stephanie, Dehay, Benjamin, Bitan, Gal, Matute, Carlos, Bezard, Erwan and Wade-Martins, Richard 2020. CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson's disease. Nature Communications 11 (1) , 4885. 10.1038/s41467-020-18689-x

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher: Nature Research
ISSN: 2041-1723
Date of First Compliant Deposit: 28 June 2021
Date of Acceptance: 27 August 2020
Last Modified: 03 May 2023 23:39

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