期刊
ANTIOXIDANTS & REDOX SIGNALING
卷 24, 期 7, 页码 376-391出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/ars.2015.6343
关键词
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资金
- Wellcome/MRC Parkinson's Disease Consortium grant
- University of Sheffield
- MRC Protein Phosphorylation Unit at University of Dundee [WT089698]
- Human Frontier Science Program Long-term Fellowship [LT000795/2009]
- Wellcome Trust
- Leverhulme Trust
- BBSRC
- European Commission [LSHM-CT-2006-037525]
- Medical Research Council (UK)
- Engineering and Physical Sciences Research Council
- Department of Health's NIHR Biomedical Research Centre's funding streams
- Wellcome Trust [106713/Z/14/Z, 100172/Z/12/Z] Funding Source: Wellcome Trust
- MRC [G0800437, MC_G1000735, G0400000] Funding Source: UKRI
- Academy of Medical Sciences (AMS) [AMS-SGCL5-Gandhi, AMS-SGCL10-Devine] Funding Source: researchfish
- Medical Research Council [MC_CF12266, MC_G1000735, G0400000, G0800437] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0513-10064, CL-2012-21-005, NF-SI-0507-10376] Funding Source: researchfish
- Parkinson's UK [H-1006] Funding Source: researchfish
- Wellcome Trust [100172/Z/12/Z, 106713/Z/14/Z] Funding Source: researchfish
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 (alpha-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 alpha-S triplication model at basal levels and on application of picomolar doses of beta-sheet-rich alpha-S oligomers. We probed the effects of different structural species of alpha-S in wild-type rat neuronal cultures and show that both oligomeric and fibrillar forms of alpha-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.
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