000095988 001__ 95988
000095988 005__ 20201028141930.0
000095988 0247_ $$2doi$$a10.1038/s41598-019-52598-4
000095988 0248_ $$2sideral$$a118588
000095988 037__ $$aART-2019-118588
000095988 041__ $$aeng
000095988 100__ $$aTóth, Gergely
000095988 245__ $$aNovel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of a-Synuclein Protect Against Diverse a-Synuclein Mediated Dysfunctions
000095988 260__ $$c2019
000095988 5060_ $$aAccess copy available to the general public$$fUnrestricted
000095988 5203_ $$aThe 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.
000095988 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000095988 590__ $$a3.998$$b2019
000095988 591__ $$aMULTIDISCIPLINARY SCIENCES$$b17 / 71 = 0.239$$c2019$$dQ1$$eT1
000095988 592__ $$a1.341$$b2019
000095988 593__ $$aMultidisciplinary$$c2019$$dQ1
000095988 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000095988 700__ $$aNeumann, Thomas
000095988 700__ $$aBerthet, Amandine
000095988 700__ $$aMasliah, Eliezer
000095988 700__ $$aSpencer, Brian
000095988 700__ $$aTao, Jiahui
000095988 700__ $$aJobling, Michael F.
000095988 700__ $$aGardai, Shyra J.
000095988 700__ $$aBertoncini, Carlos W.
000095988 700__ $$0(orcid)0000-0002-9138-6687$$aCremades, Nunilo$$uUniversidad de Zaragoza
000095988 700__ $$aBova, Michael
000095988 700__ $$aBallaron, Stephen
000095988 700__ $$aChen, Xiao-Hua
000095988 700__ $$aMao, Wenxian
000095988 700__ $$aNguyen, Phuong
000095988 700__ $$aTabios, Mariano C.
000095988 700__ $$aTambe, Mitali A.
000095988 700__ $$aRochet, Jean-Christophe
000095988 700__ $$aJunker, Hans-Dieter
000095988 700__ $$aSchwizer, Daniel
000095988 700__ $$aSekul, Renate
000095988 700__ $$aOtt, Inge
000095988 700__ $$aAnderson, John P.
000095988 700__ $$aSzoke, Balazs
000095988 700__ $$aHoffman, Wherly
000095988 700__ $$aChristodoulou, John
000095988 700__ $$aYednock, Ted
000095988 700__ $$aAgard, David A.
000095988 700__ $$aSchenk, Dale
000095988 700__ $$aMcConlogue, Lisa
000095988 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000095988 773__ $$g9, 1 (2019), 16947 [14 pp]$$pSci. rep.$$tScientific Reports$$x2045-2322
000095988 8564_ $$s2507715$$uhttps://zaguan.unizar.es/record/95988/files/texto_completo.pdf$$yVersión publicada
000095988 8564_ $$s369031$$uhttps://zaguan.unizar.es/record/95988/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000095988 909CO $$ooai:zaguan.unizar.es:95988$$particulos$$pdriver
000095988 951__ $$a2020-10-28-13:18:44
000095988 980__ $$aARTICLE