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Lookup NU author(s): Professor Tiago OuteiroORCiD
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© 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.
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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