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CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease

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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522721/
https://www.ncbi.nlm.nih.gov/pubmed/32985503
http://dx.doi.org/10.1038/s41467-020-18689-x
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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
author_facet 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
author_sort Bengoa-Vergniory, Nora
collection PubMed
description 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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spelling pubmed-75227212020-10-19 CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease 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 Nat Commun Article 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. Nature Publishing Group UK 2020-09-28 /pmc/articles/PMC7522721/ /pubmed/32985503 http://dx.doi.org/10.1038/s41467-020-18689-x Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
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
CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease
title CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease
title_full CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease
title_fullStr CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease
title_full_unstemmed CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease
title_short CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease
title_sort clr01 protects dopaminergic neurons in vitro and in mouse models of parkinson’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522721/
https://www.ncbi.nlm.nih.gov/pubmed/32985503
http://dx.doi.org/10.1038/s41467-020-18689-x
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