Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein Protect Against Diverse α-Synuclein Mediated Dysfunctions.
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Authors
Tóth, Gergely
Neumann, Thomas
Berthet, Amandine
Masliah, Eliezer
Spencer, Brian
Tao, Jiahui
Jobling, Michael F
Gardai, Shyra J
Bertoncini, Carlos W
Bova, Michael
Ballaron, Stephen
Chen, Xiao-Hua
Mao, Wenxian
Nguyen, Phuong
Tabios, Mariano C
Tambe, Mitali A
Rochet, Jean-Christophe
Junker, Hans-Dieter
Schwizer, Daniel
Sekul, Renate
Ott, Inge
Anderson, John P
Szoke, Balazs
Hoffman, Wherly
Christodoulou, John
Yednock, Ted
Schenk, Dale
McConlogue, Lisa
Publication Date
2019-11-18ISSN
2045-2322
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Tóth, G., Neumann, T., Berthet, A., Masliah, E., Spencer, B., Tao, J., Jobling, M. F., et al. (2019). Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein Protect Against Diverse α-Synuclein Mediated Dysfunctions.. https://doi.org/10.1038/s41598-019-52598-4
Abstract
The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson's disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson's disease.
Sponsorship
Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) (NS049221, R21NS092897)
NINDS NIH HHS (R01 NS049221, R21 NS092897)
Identifiers
31740740, PMC6861283
External DOI: https://doi.org/10.1038/s41598-019-52598-4
This record's URL: https://www.repository.cam.ac.uk/handle/1810/300238