학술논문
CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson's disease.
Document Type
article
Author
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
Source
Nature communications. 11(1)
Subject
Language
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.