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Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):10481-10486. doi: 10.1073/pnas.1804198115. Epub 2018 Sep 24.

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

Author information

1
Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
2
Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
3
Department of Experimental Neurodegeneration, University Medical Center Göttingen, 37073 Göttingen, Germany.
4
Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, 37073 Göttingen, Germany.
5
Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, 37073 Göttingen, Germany.
6
Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
7
Laboratoire de Chimie Théorique, Sorbonne Universités, CNRS, F-75005 Paris, France.
8
Department of Biochemistry and Molecular and Cell Biology, University of Zaragoza, 50018 Zaragoza, Spain.
9
Institute for Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, 50018 Zaragoza, Spain.
10
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain.
11
Department of Inorganic and Organic Chemistry, University of Barcelona, 08028 Spain.
12
Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.
13
Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany.
14
Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
15
Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), 08500 Vic, Spain.
16
Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
17
Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; salvador.ventura@uab.es.

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.

KEYWORDS:

Parkinson’s disease; aggregation inhibition; dopaminergic degeneration; protein aggregation; α-synuclein

PMID:
30249646
PMCID:
PMC6187188
[Available on 2019-04-09]
DOI:
10.1073/pnas.1804198115
[Indexed for MEDLINE]

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