Alpha-synuclein oligomers interact with metal ions to induce oxidative stress and neuronal death in Parkinson's disease

Deas, E. ; Cremades, N. (Universidad de Zaragoza) ; 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.

Resumen: 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.

Idioma: Inglés

DOI: 10.1089/ars.2015.6343

Año: 2016

Publicado en: Antioxidants & redox signaling 24, 7 (2016), 376-391
ISSN: 1523-0864

Factor impacto JCR: 6.337 (2016)

Categ. JCR: ENDOCRINOLOGY & METABOLISM rank: 13 / 138 = 0.094 (2016) - Q1 - T1
Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 34 / 287 = 0.118 (2016) - Q1 - T1

Factor impacto SCIMAGO: 2.896 - Biochemistry (Q1) - Cell Biology (Q1) - Physiology (Q1) - Medicine (miscellaneous) (Q1) - Molecular Biology (Q1) - Clinical Biochemistry (Q1)

Financiación: info:eu-repo/grantAgreement/EUR/FP6/LSHM-CT-2006-037525

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)