000097144 001__ 97144 000097144 005__ 20210902121852.0 000097144 0247_ $$2doi$$a10.1039/d0sc05297c 000097144 0248_ $$2sideral$$a121118 000097144 037__ $$aART-2020-121118 000097144 041__ $$aeng 000097144 100__ $$0(orcid)0000-0002-7848-5373$$aCamino, J.D.$$uUniversidad de Zaragoza 000097144 245__ $$aThe extent of protein hydration dictates the preference for heterogeneous or homogeneous nucleation generating either parallel or antiparallel ß-sheet a-synuclein aggregates 000097144 260__ $$c2020 000097144 5060_ $$aAccess copy available to the general public$$fUnrestricted 000097144 5203_ $$aa-Synuclein amyloid self-assembly is the hallmark of a number of neurodegenerative disorders, including Parkinson 's disease, although there is still very limited understanding about the factors and mechanisms that trigger this process. Primary nucleation has been observed to be initiated in vitro at hydrophobic/hydrophilic interfaces by heterogeneous nucleation generating parallel ß-sheet aggregates, although no such interfaces have yet been identified in vivo. In this work, we have discovered that a-synuclein can self-assemble into amyloid aggregates by homogeneous nucleation, without the need of an active surface, and with a preference for an antiparallel ß-sheet arrangement. This particular structure has been previously proposed to be distinctive of stable toxic oligomers and we here demonstrate that it indeed represents the most stable structure of the preferred amyloid pathway triggered by homogeneous nucleation under limited hydration conditions, including those encountered inside a-synuclein droplets generated by liquid-liquid phase separation. In addition, our results highlight the key role that water plays not only in modulating the transition free energy of amyloid nucleation, and thus governing the initiation of the process, but also in dictating the type of preferred primary nucleation and the type of amyloid polymorph generated depending on the extent of protein hydration. These findings are particularly relevant in the context of in vivo a-synuclein aggregation where the protein can encounter a variety of hydration conditions in different cellular microenvironments, including the vicinity of lipid membranes or the interior of membraneless compartments, which could lead to the formation of remarkably different amyloid polymorphs by either heterogeneous or homogeneous nucleation. 000097144 536__ $$9info:eu-repo/grantAgreement/ES/MCIU-FEDER/PGC2018-096335-B-100$$9info:eu-repo/grantAgreement/ES/MCIU-FEDER/RTI2018-099019-A-I00$$9info:eu-repo/grantAgreement/ES/MINECO-FEDER/BFU2015-64119-P$$9info:eu-repo/grantAgreement/ES/MINECO/RYC-2012-12068 000097144 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc$$uhttp://creativecommons.org/licenses/by-nc/3.0/es/ 000097144 590__ $$a9.825$$b2020 000097144 591__ $$aCHEMISTRY, MULTIDISCIPLINARY$$b22 / 178 = 0.124$$c2020$$dQ1$$eT1 000097144 592__ $$a3.686$$b2020 000097144 593__ $$aChemistry (miscellaneous)$$c2020$$dQ1 000097144 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000097144 700__ $$aGracia, P. 000097144 700__ $$aChen, S.W. 000097144 700__ $$aSot, J. 000097144 700__ $$aDe La Arada, I. 000097144 700__ $$0(orcid)0000-0002-6873-5244$$aSebastián, V.$$uUniversidad de Zaragoza 000097144 700__ $$aArrondo, J.L.R. 000097144 700__ $$aGoñi, F.M. 000097144 700__ $$aDobson, C.M. 000097144 700__ $$0(orcid)0000-0002-9138-6687$$aCremades, N.$$uUniversidad de Zaragoza 000097144 7102_ $$15005$$2555$$aUniversidad de Zaragoza$$bDpto. Ing.Quím.Tecnol.Med.Amb.$$cÁrea Ingeniería Química 000097144 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole. 000097144 773__ $$g11, 43 (2020), 11902-11914$$pChem. sci.$$tChemical Science$$x2041-6520 000097144 8564_ $$s488490$$uhttps://zaguan.unizar.es/record/97144/files/texto_completo.pdf$$yVersión publicada 000097144 8564_ $$s68088$$uhttps://zaguan.unizar.es/record/97144/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000097144 909CO $$ooai:zaguan.unizar.es:97144$$particulos$$pdriver 000097144 951__ $$a2021-09-02-10:30:01 000097144 980__ $$aARTICLE