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, Richard Wade-Martins
Nat Commun. 2020-09-28; 11(1):
DOI: 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.

Auteurs Bordeaux Neurocampus