CLR01 Protects Dopaminergic Neurons in Vitro and in Mouse Models of Parkinson's Disease

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Sep 28

PMID 32985503

Citations 35

Authors

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 Klarner

Stephanie Cragg

Benjamin Dehay

Gal Bitan

Carlos Matute

Erwan Bezard

Richard Wade-Martins

Affiliations

Soon will be listed here.

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.

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