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 Brown, Ibrar Siddique, Zizheng Li, Siv Vingill, Milena Cioroch, Fabio Cavaliere, Sarah Threlfell, Bradley M. Roberts, Thomas Schräder, Frank‐Gerrit Klärner, Stephanie J. Cragg, Benjamin Dehay, Gal Bitan, Carlos Matute, Erwan Bézard, Richard Wade‐Martins
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.