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Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons

Lookup NU author(s): Professor Tiago Outeiro

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Abstract

© 2018 Proceedings of the National Academy of Sciences of the United States of America. All rights reserved. Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of intracellular protein inclusions, known as Lewy bodies and Lewy neurites, which are mainly composed of α-synuclein. Here, we exploited a high-throughput screeningmethodology to identify a smallmolecule (SynuClean-D) able to inhibit α-synuclein aggregation. SynuClean-D significantly reduces the in vitro aggregation of wildtype α-synuclein and the familiar A30P and H50Q variants in a substoichiometric molar ratio. This compound prevents fibril propagation in protein-misfolding cyclic amplification assays and decreases the number of α-synuclein inclusions in human neuroglioma cells. Computational analysis suggests that SynuClean-D can bind to cavities in mature α-synuclein fibrils and, indeed, it displays a strong fibril disaggregation activity. The treatment with SynuClean-D of two PD Caenorhabditis elegans models, expressing α-synuclein either in muscle or in dopaminergic neurons, significantly reduces the toxicity exerted by α-synuclein. SynuClean-D-treated worms show decreased α-synuclein aggregation in muscle and a concomitant motility recovery. More importantly, this compound is able to rescue dopaminergic neurons from α-synuclein-induced degeneration. Overall, SynuClean-D appears to be a promising molecule for therapeutic intervention in Parkinson's disease.


Publication metadata

Author(s): Pujols J, Pena-Diaz S, Lazaro DF, Peccati F, Pinheiro F, Gonzalez D, Carija A, Navarro S, Conde-Gimenez M, Garcia J, Guardiola S, Giralt E, Salvatella X, Sancho J, Sodupe M, Outeiro TF, Dalfo E, Ventura S

Publication type: Article

Publication status: Published

Journal: Proceedings of the National Academy of Sciences of the United States of America

Year: 2018

Volume: 115

Issue: 41

Pages: 10481-10486

Print publication date: 09/10/2018

Online publication date: 24/09/2018

Acceptance date: 16/08/2018

ISSN (print): 0027-8424

ISSN (electronic): 1091-6490

Publisher: National Academy of Sciences

URL: https://doi.org/10.1073/pnas.1804198115

DOI: 10.1073/pnas.1804198115

PubMed id: 30249646


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