000097191 001__ 97191
000097191 005__ 20210902121917.0
000097191 0247_ $$2doi$$a10.3389/fbioe.2020.588947
000097191 0248_ $$2sideral$$a120957
000097191 037__ $$aART-2020-120957
000097191 041__ $$aeng
000097191 100__ $$aPeña-Díaz, S.
000097191 245__ $$aInhibition of a-Synuclein Aggregation and Mature Fibril Disassembling With a Minimalistic Compound, ZPDm
000097191 260__ $$c2020
000097191 5060_ $$aAccess copy available to the general public$$fUnrestricted
000097191 5203_ $$aSynucleinopathies are a group of disorders characterized by the accumulation of a-Synuclein amyloid inclusions in the brain. Preventing a-Synuclein aggregation is challenging because of the disordered nature of the protein and the stochastic nature of fibrillogenesis, but, at the same time, it is a promising approach for therapeutic intervention in these pathologies. A high-throughput screening initiative allowed us to discover ZPDm, the smallest active molecule in a library of more than 14.000 compounds. Although the ZPDm structure is highly related to that of the previously described ZPD-2 aggregation inhibitor, we show here that their mechanisms of action are entirely different. ZPDm inhibits the aggregation of wild-type, A30P, and H50Q a-Synuclein variants in vitro and interferes with a-Synuclein seeded aggregation in protein misfolding cyclic amplification assays. However, ZPDm distinctive feature is its strong potency to dismantle preformed a-Synuclein amyloid fibrils. Studies in a Caenorhabditis elegans model of Parkinson’s Disease, prove that these in vitro properties are translated into a significant reduction in the accumulation of a-Synuclein inclusions in ZPDm treated animals. Together with previous data, the present work illustrates how different chemical groups on top of a common molecular scaffold can result in divergent but complementary anti-amyloid activities.
000097191 536__ $$9info:eu-repo/grantAgreement/ES/DGA/E45-17R$$9info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P
000097191 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000097191 590__ $$a5.89$$b2020
000097191 591__ $$aMULTIDISCIPLINARY SCIENCES$$b12 / 73 = 0.164$$c2020$$dQ1$$eT1
000097191 592__ $$a1.081$$b2020
000097191 593__ $$aBioengineering$$c2020$$dQ1
000097191 593__ $$aHistology$$c2020$$dQ1
000097191 593__ $$aBiotechnology$$c2020$$dQ1
000097191 593__ $$aBiomedical Engineering$$c2020$$dQ1
000097191 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000097191 700__ $$aPujols, J.
000097191 700__ $$aPinheiro, F.
000097191 700__ $$aSantos, J.
000097191 700__ $$aPallarés, I.
000097191 700__ $$aNavarro, S.
000097191 700__ $$0(orcid)0000-0003-4358-9110$$aConde-Gimenez, M.
000097191 700__ $$aGarcía, J.
000097191 700__ $$aSalvatella, X.
000097191 700__ $$aDalfó, E.
000097191 700__ $$0(orcid)0000-0002-2879-9200$$aSancho, J.$$uUniversidad de Zaragoza
000097191 700__ $$aVentura, S.
000097191 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000097191 773__ $$g8 (2020), 588947 [12 pp]$$pFront. Bioeng. Biotechnol.$$tFrontiers in Bioengineering and Biotechnology$$x2296-4185
000097191 8564_ $$s449838$$uhttps://zaguan.unizar.es/record/97191/files/texto_completo.pdf$$yVersión publicada
000097191 8564_ $$s487212$$uhttps://zaguan.unizar.es/record/97191/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
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000097191 951__ $$a2021-09-02-10:46:21
000097191 980__ $$aARTICLE