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- Title
CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson's disease.
- Authors
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
- 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. CLR01 is a molecular tweezer that inhibits protein aggregation. Here the authors show that CLR01 protects dopaminergic neurons in vitro and in vivo in human neurons and in mouse models showing potential as a disease-modifying therapy for Parkinson's disease.
- Subjects
DOPAMINERGIC neurons; PARKINSON'S disease; PLURIPOTENT stem cells; CELL aggregation; SUBSTANTIA nigra; MICROFLUIDIC devices; MICE
- Publication
Nature Communications, 2020, Vol 11, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-18689-x