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Edited by Gregory A. Petsko, Weill Cornell Medical College, New York, NY, and approved August 16, 2018 (received for review April 3, 2018)
Significance
Parkinson’s disease is characterized by the accumulation of amyloid deposits in dopaminergic neurons, mainly composed of the protein α-synuclein. The disordered nature of α-synuclein and its complex aggregation reaction complicate the identification of molecules able to prevent or revert the formation of these inclusions and the subsequent neurodegeneration. By exploiting a recently developed high-throughput screening assay, we identified SynuClean-D, a small compound that inhibits α-synuclein aggregation, disrupts mature amyloid fibrils, prevents fibril propagation, and abolishes the degeneration of dopaminergic neurons in an animal model of Parkinson’s disease.
Abstract
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 screening methodology to identify a small molecule (SynuClean-D) able to inhibit α-synuclein aggregation. SynuClean-D significantly reduces the in vitro aggregation of wild-type 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.
Footnotes
↵1J.P. and S.P.-D. contributed equally to this work.
- ↵2To whom correspondence should be addressed. Email: salvador.ventura{at}uab.es.
Author contributions: S.V. designed research; J.P., S.P.-D., D.F.L., F. Peccati, F. Pinheiro, D.G., A.C., S.N., M.C.-G., J.G., S.G., and E.D. performed research; J.P., S.P.-D., D.F.L., E.G., X.S., J.S., M.S., T.F.O., E.D., and S.V. analyzed data; and M.S., E.D., and S.V. wrote the paper.
Conflict of interest statement: J.P., S.P.-D., M.C.-G., J.S., E.D., and S.V. are inventors on a patent application (PCT/EP2018/054540) related to the compound in this study.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1804198115/-/DCSupplemental.
Published under the PNAS license.
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Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons
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