000075810 001__ 75810
000075810 005__ 20191212102146.0
000075810 0247_ $$2doi$$a10.1073/pnas.1804198115
000075810 0248_ $$2sideral$$a108518
000075810 037__ $$aART-2018-108518
000075810 041__ $$aeng
000075810 100__ $$aPujols, J.
000075810 245__ $$aSmall molecule inhibits alpha-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons
000075810 260__ $$c2018
000075810 5060_ $$aAccess copy available to the general public$$fUnrestricted
000075810 5203_ $$aParkinson''s disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of intracellular protein inclusions, known as Lewy bodies and Lewy neurites, which are mainly composed of alpha-synuclein. Here, we exploited a high-throughput screening methodology to identify a small molecule (SynuClean-D) able to inhibit alpha-synuclein aggregation. SynuClean-D significantly reduces the in vitro aggregation of wildtype alpha-synuclein and the familiar A30P and H50Q variants in a substoichiometric molar ratio. This compound prevents fibril propagation in protein-misfolding cyclic amplification assays and decreases the number of alpha-synuclein inclusions in human neuroglioma cells. Computational analysis suggests that SynuClean-D can bind to cavities in mature alpha-synuclein fibrils and, indeed, it displays a strong fibril disaggregation activity. The treatment with SynuClean-D of two PD Caenorhabditis elegans models, expressing alpha-synuclein either in muscle or in dopaminergic neurons, significantly reduces the toxicity exerted by alpha- synuclein. SynuClean-D-treated worms show decreased alpha-synuclein aggregation in muscle and a concomitant motility recovery. More importantly, this compound is able to rescue dopaminergic neurons from alpha-synuclein-induced degeneration. Overall, SynuClean-D appears to be a promising molecule for therapeutic intervention in Parkinson's disease.
000075810 536__ $$9info:eu-repo/grantAgreement/ES/DGA/E45-17R$$9info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P
000075810 540__ $$9info:eu-repo/semantics/openAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/
000075810 590__ $$a9.58$$b2018
000075810 591__ $$aMULTIDISCIPLINARY SCIENCES$$b7 / 69 = 0.101$$c2018$$dQ1$$eT1
000075810 592__ $$a5.601$$b2018
000075810 593__ $$aMultidisciplinary$$c2018$$dQ1
000075810 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000075810 700__ $$aPena-Diaz, S.
000075810 700__ $$aLazaro, D.F.
000075810 700__ $$aPeccati, F.
000075810 700__ $$aPinheiro, F.
000075810 700__ $$aGonzalez, D.
000075810 700__ $$aCarija, A.
000075810 700__ $$aNavarro, S.
000075810 700__ $$0(orcid)0000-0003-4358-9110$$aConde-Gimenez, M.
000075810 700__ $$aGarcia, J.
000075810 700__ $$aGuardiola, S.
000075810 700__ $$aGiralt, E.
000075810 700__ $$aSalvatella, X.
000075810 700__ $$0(orcid)0000-0002-2879-9200$$aSancho, J.$$uUniversidad de Zaragoza
000075810 700__ $$aSodupe, M.
000075810 700__ $$aOuteiro, T.F.
000075810 700__ $$aDalfo, E.
000075810 700__ $$aVentura, S.
000075810 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000075810 773__ $$g115, 41 (2018), 10481-10486$$pProc. Natl. Acad. Sci.$$tProceedings of the National Academy of Sciences$$x0027-8424
000075810 8564_ $$s818407$$uhttps://zaguan.unizar.es/record/75810/files/texto_completo.pdf$$yVersión publicada
000075810 8564_ $$s146308$$uhttps://zaguan.unizar.es/record/75810/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000075810 909CO $$ooai:zaguan.unizar.es:75810$$particulos$$pdriver
000075810 951__ $$a2019-12-12-10:15:08
000075810 980__ $$aARTICLE