000075453 001__ 75453
000075453 005__ 20210526094558.0
000075453 0247_ $$2doi$$a10.1089/ars.2015.6343
000075453 0248_ $$2sideral$$a107781
000075453 037__ $$aART-2016-107781
000075453 041__ $$aeng
000075453 100__ $$aDeas, E.
000075453 245__ $$aAlpha-synuclein oligomers interact with metal ions to induce oxidative stress and neuronal death in Parkinson's disease
000075453 260__ $$c2016
000075453 5060_ $$aAccess copy available to the general public$$fUnrestricted
000075453 5203_ $$aAims: Protein aggregation and oxidative stress are both key pathogenic processes in Parkinson's disease, although the mechanism by which misfolded proteins induce oxidative stress and neuronal death remains unknown. In this study, we describe how aggregation of alpha-synuclein (a-S) from its monomeric form to its soluble oligomeric state results in aberrant free radical production and neuronal toxicity. Results: We first demonstrate excessive free radical production in a human induced pluripotent stem-derived a-S triplication model at basal levels and on application of picomolar doses of ß-sheet-rich a-S oligomers. We probed the effects of different structural species of a-S in wild-type rat neuronal cultures and show that both oligomeric and fibrillar forms of a-S are capable of generating free radical production, but that only the oligomeric form results in reduction of endogenous glutathione and subsequent neuronal toxicity. We dissected the mechanism of oligomer-induced free radical production and found that it was interestingly independent of several known cellular enzymatic sources. Innovation: The oligomer-induced reactive oxygen species (ROS) production was entirely dependent on the presence of free metal ions as addition of metal chelators was able to block oligomer-induced ROS production and prevent oligomer-induced neuronal death. Conclusion: Our findings further support the causative role of soluble amyloid oligomers in triggering neurodegeneration and shed light into the mechanisms by which these species cause neuronal damage, which, we show here, can be amenable to modulation through the use of metal chelation. Antioxid. Redox Signal. 24, 376–391.
000075453 536__ $$9info:eu-repo/grantAgreement/EUR/FP6/LSHM-CT-2006-037525
000075453 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000075453 590__ $$a6.337$$b2016
000075453 591__ $$aENDOCRINOLOGY & METABOLISM$$b13 / 138 = 0.094$$c2016$$dQ1$$eT1
000075453 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b34 / 287 = 0.118$$c2016$$dQ1$$eT1
000075453 592__ $$a2.896$$b2016
000075453 593__ $$aBiochemistry$$c2016$$dQ1
000075453 593__ $$aCell Biology$$c2016$$dQ1
000075453 593__ $$aPhysiology$$c2016$$dQ1
000075453 593__ $$aMedicine (miscellaneous)$$c2016$$dQ1
000075453 593__ $$aMolecular Biology$$c2016$$dQ1
000075453 593__ $$aClinical Biochemistry$$c2016$$dQ1
000075453 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000075453 700__ $$0(orcid)0000-0002-9138-6687$$aCremades, N.$$uUniversidad de Zaragoza
000075453 700__ $$aAngelova, P.R.
000075453 700__ $$aLudtmann, M.
000075453 700__ $$aYao, Z.
000075453 700__ $$aChen, S.W.
000075453 700__ $$aHorrocks, M.H.
000075453 700__ $$aBanushi, B.
000075453 700__ $$aLittle, D.
000075453 700__ $$aDevine, M.
000075453 700__ $$aGissen, P.
000075453 700__ $$aKlenerman, D.
000075453 700__ $$aDobson, C.M.
000075453 700__ $$aWood, N.W.
000075453 700__ $$aGandhi, S.
000075453 700__ $$aAbramov, A.Y.
000075453 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000075453 773__ $$g24, 7 (2016), 376-391$$pAntioxid. redox signal.$$tAntioxidants & redox signaling$$x1523-0864
000075453 8564_ $$s1130768$$uhttps://zaguan.unizar.es/record/75453/files/texto_completo.pdf$$yVersión publicada
000075453 8564_ $$s113209$$uhttps://zaguan.unizar.es/record/75453/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
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000075453 951__ $$a2021-05-26-09:31:54
000075453 980__ $$aARTICLE