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Genome-Wide Microarray Analysis of the Differential Neuroprotective Effects of Antioxidants in Neuroblastoma Cells Overexpressing the Familial Parkinson’s Disease α-Synuclein A53T Mutation

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Abstract

In Parkinson’s disease substantia nigra neurons degenerate likely due to oxidative damage interacting with genetic risk factors. Here, SH-SY5Y cells expressing wild-type or A53T α-synuclein had increased sensitivity to methyl-4-phenylpyridinium iodide (MPP+), which induces mitochondrial dysfunction, and 6-hydroxydopamine (6-OHDA), which causes oxidative stress. Edaravone protected only against MPP+, and EGCG ((−)-epigallocatechin-3-O-gallate) protected only against 6-OHDA. Thus genomic responses to MPP+ and 6-OHDA in the presence of these antioxidants were analyzed using microarrays. Pathway analysis indicated that MPP+ activated p53 (P < 0.001) while 6-OHDA induced the Nrf2 antioxidative stress response (P < 0.0001). EGCG was more effective at blocking 6-OHDA-mediated genomic responses, while edaravone was more effective against MPP+. We identified 32 genes that responded to both toxins except in the presence of an effective anti-oxidant; eight are transcription factors and potentially constitute a stress-response transcriptional network. These data provide insights into the mechanisms of neurotoxicity and identifies genes that might mediate antioxidant efficacy.

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Acknowledgments

The authors thank Dr. Ian Reynolds for advice during the preparation of the manuscript.

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Authors and Affiliations

  1. WP Alzheimer’s, Merck Research Laboratories, P.O. Box 4, WP26A-2000, West Point, PA, 19486-0004, USA

    Lei Ma, Tracy T. Cao, Guy R. Seabrook & William J. Ray

  2. WP Stroke & Neurodegeneration, Merck Research Laboratories, West Point, PA, USA

    Geeta Kandpal & J. Fred Hess

  3. Boston Neuroscience Drug Discovery, Merck Research Laboratories, West Point, PA, USA

    Lee Warren

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  1. Lei Ma
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  2. Tracy T. Cao
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  3. Geeta Kandpal
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Correspondence to Lei Ma.

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Lei Ma and Tracy T. Cao have contributed equally to this work.

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Ma, L., Cao, T.T., Kandpal, G. et al. Genome-Wide Microarray Analysis of the Differential Neuroprotective Effects of Antioxidants in Neuroblastoma Cells Overexpressing the Familial Parkinson’s Disease α-Synuclein A53T Mutation. Neurochem Res 35, 130–142 (2010). https://doi.org/10.1007/s11064-009-0038-1

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