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dc.contributor.authorTóth, Gergely
dc.contributor.authorNeumann, Thomas
dc.contributor.authorBerthet, Amandine
dc.contributor.authorMasliah, Eliezer
dc.contributor.authorSpencer, Brian
dc.contributor.authorTao, Jiahui
dc.contributor.authorJobling, Michael F
dc.contributor.authorGardai, Shyra J
dc.contributor.authorBertoncini, Carlos W
dc.contributor.authorCremades, Nunilo
dc.contributor.authorBova, Michael
dc.contributor.authorBallaron, Stephen
dc.contributor.authorChen, Xiao-Hua
dc.contributor.authorMao, Wenxian
dc.contributor.authorNguyen, Phuong
dc.contributor.authorTabios, Mariano C
dc.contributor.authorTambe, Mitali A
dc.contributor.authorRochet, Jean-Christophe
dc.contributor.authorJunker, Hans-Dieter
dc.contributor.authorSchwizer, Daniel
dc.contributor.authorSekul, Renate
dc.contributor.authorOtt, Inge
dc.contributor.authorAnderson, John P
dc.contributor.authorSzoke, Balazs
dc.contributor.authorHoffman, Wherly
dc.contributor.authorChristodoulou, John
dc.contributor.authorYednock, Ted
dc.contributor.authorAgard, David A
dc.contributor.authorSchenk, Dale
dc.contributor.authorMcConlogue, Lisa
dc.date.accessioned2019-12-21T01:34:36Z
dc.date.available2019-12-21T01:34:36Z
dc.date.issued2019-11-18
dc.identifier.issn2045-2322
dc.identifier.other31740740
dc.identifier.otherPMC6861283
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/300238
dc.description.abstractThe 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.
dc.languageeng
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourcenlmid: 101563288
dc.sourceessn: 2045-2322
dc.titleNovel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein Protect Against Diverse α-Synuclein Mediated Dysfunctions.
dc.typeArticle
dc.date.updated2019-12-21T01:34:35Z
dc.identifier.doi10.17863/CAM.47311
rioxxterms.versionofrecord10.1038/s41598-019-52598-4
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidCremades, Nunilo [0000-0002-9138-6687]
dc.contributor.orcidAgard, David A [0000-0003-3512-695X]
pubs.funder-project-idFoundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) (NS049221, R21NS092897)
pubs.funder-project-idNINDS NIH HHS (R01 NS049221, R21 NS092897)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International