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Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson’s Disease
Open accessAbstract
The misfolding of intrinsically disordered proteins such as α-synuclein, tau and the Aβ peptide has been associated with many highly debilitating neurodegenerative syndromes including Parkinson's and Alzheimer's diseases. Therapeutic targeting of the monomeric state of such intrinsically disordered proteins by small molecules has, however, been a major challenge because of their heterogeneous conformational properties. We show here that a combination of computational and experimental techniques has led to the identification of a drug-like phenyl-sulfonamide compound (ELN484228), that targets α-synuclein, a key protein in Parkinson's disease. We found that this compound has substantial biological activity in cellular models of α-synuclein-mediated dysfunction, including rescue of α-synuclein-induced disruption of vesicle trafficking and dopaminergic neuronal loss and neurite retraction most likely by reducing the amount of α-synuclein targeted to sites of vesicle mobilization such as the synapse in neurons or the site of bead engulfment in microglial cells. These results indicate that targeting α-synuclein by small molecules represents a promising approach to the development of therapeutic treatments of Parkinson's disease and related conditions.
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“Targeting the intrinsically disordered structural ensemble of α-synuclein by small molecules as a potential therapeutic strategy for Parkinson’s disease has been shown to be promising.429”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [429]
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Metadata
- Authors
- Tóth, G., Gardai, S. J., Zago, W., Bertoncini, C. W., Cremades, N., Roy, S. L., Tambe, M. A., Rochet, J.-C., Galvagnion, C., Skibinski, G., Finkbeiner, S., Bova, M., Regnstrom, K., Chiou, S.-S., Johnston, J., Callaway, K., Anderson, J. P., Jobling, M. F., Buell, A. K., Yednock, T. A., Knowles, T. P. J., Vendruscolo, M., Christodoulou, J., Dobson, C. M., Schenk, D., & McConlogue, L.
- Affiliations
- University of Cambridge (GB)
- Elan Pharmaceuticals, Inc. (Ireland) (IE)
- Purdue University West Lafayette (US)
- Gladstone Institutes (US)
- University College London (GB)
- Corresponding author
- Tóth, Gergely
- Vendruscolo, Michele
- Dobson, Christopher M.
- Schenk, Dale
- McConlogue, Lisa
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-02-14
- Volume
- 9
- Issue
- 2
- Pages
- e87133
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3925190
- OpenAlex
- W2145653859
- Cited by
- 151
- References
- 70
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 7 · 2023: 11 · 2022: 9 · 2021: 12 · 2020: 16 · 2019: 7 · 2018: 19 · 2017: 16 · 2016: 18 · 2015: 12 · 2014: 10
- FWCI
- 12.10
- Type
- journal article
- Language
- en
- Update notices
- correction (2014-05-27)
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
- Americanae (AECID Library) (submittedVersion, cc-by-nc-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Greater South Information System
- Funders
- Wellcome Trust (097806)
- University of Cambridge
- Ministerio de Ciencia e Innovación
- National Institutes of Health
- Medical Research Council (MC_G1000734)
- Biotechnology and Biological Sciences Research Council (BB/H003843/1)
- National Institute of Neurological Disorders and Stroke (R01NS039074, R01NS083390)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- alpha-synuclein, Parkinson's disease, intrinsically disordered proteins, small molecule drug candidates, protein misfolding, vesicle trafficking, dopaminergic neurons, neurite retraction, microglia, synapses, drug repurposing
- MeSH terms
- Animals, Binding Sites, Humans, Models, Biological, Models, Molecular, Nerve Degeneration, Parkinson Disease, Phagocytes, Synapses, Mice, alpha-Synuclein, Small Molecule Libraries, Molecular Targeted Therapy, Dopaminergic Neurons, Intrinsically Disordered Proteins
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