75453 20210526094558.0 doi 10.1089/ars.2015.6343 sideral 107781 ART-2016-107781 eng Deas, E. Alpha-synuclein oligomers interact with metal ions to induce oxidative stress and neuronal death in Parkinson's disease 2016 Access copy available to the general public Unrestricted Aims: 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. info:eu-repo/grantAgreement/EUR/FP6/LSHM-CT-2006-037525 info:eu-repo/semantics/openAccess by http://creativecommons.org/licenses/by/3.0/es/ 6.337 2016 ENDOCRINOLOGY & METABOLISM 13 / 138 = 0.094 2016 Q1 T1 BIOCHEMISTRY & MOLECULAR BIOLOGY 34 / 287 = 0.118 2016 Q1 T1 2.896 2016 Biochemistry 2016 Q1 Cell Biology 2016 Q1 Physiology 2016 Q1 Medicine (miscellaneous) 2016 Q1 Molecular Biology 2016 Q1 Clinical Biochemistry 2016 Q1 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Cremades, N. Universidad de Zaragoza (orcid)0000-0002-9138-6687 Angelova, P.R. Ludtmann, M. Yao, Z. Chen, S.W. Horrocks, M.H. Banushi, B. Little, D. Devine, M. Gissen, P. Klenerman, D. Dobson, C.M. Wood, N.W. Gandhi, S. Abramov, A.Y. 1002 060 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Bioquímica y Biolog.Mole. 24, 7 (2016), 376-391 Antioxid. redox signal. Antioxidants & redox signaling 1523-0864 1130768 http://zaguan.unizar.es/record/75453/files/texto_completo.pdf Versión publicada 113209 http://zaguan.unizar.es/record/75453/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:75453 articulos driver 2021-05-26-09:31:54 ARTICLE