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

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Bengoa-Vergniory, Nora | Faggiani, Emilie | Ramos-Gonzalez, Paula | Kirkiz, Ecem | Connor-Robson, Natalie | 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 | Wade-Martins, Richard

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

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