Cited by 151Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsProtein Structure and Dynamics

Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson’s Disease

Open access
Tóth, Gergely, Gardai, Shyra J., Zago, Wagner, Bertoncini, Carlos W., Cremades, Nunilo, Roy, Susan L., Tambe, Mitali A., Rochet, Jean-Christophe +18 more·2014·PLoS ONE

Abstract

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0087133

Cites

69 of 69 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

1 of the 70 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

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
Venue
PLoS ONE
Published
2014-02-14
Volume
9
Issue
2
Pages
e87133
ISSN
1932-6203 (ISSN-L)
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
Open access
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 › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Physiology › 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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review