Genome-wide microarray analysis of the differential neuroprotective effects of antioxidants in neuroblastoma cells overexpressing the familial Parkinson's disease alpha-synuclein A53T mutation.

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 alpha-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.

• Authors: Lei Ma, Tracy T Cao, Geeta Kandpal, Lee Warren, J Fred Hess, Guy R Seabrook, William J Ray
• Journal: Neurochemical research (Neurochem Res) Vol. 35 Issue 1 Pg. 130-42 (Jan 2010) ISSN: 1573-6903 [Electronic] United States
• PMID: 19649707 (Publication Type: Journal Article)

Chemical References

• Antioxidants
• DNA Primers
• alpha-Synuclein

Topics

• Antioxidants (metabolism)
• Base Sequence
• Blotting, Western
• Cell Line, Tumor
• DNA Primers
• Genome
• Humans
• Mutation
• Neuroblastoma (genetics, metabolism, pathology)
• Oligonucleotide Array Sequence Analysis
• Parkinson Disease (genetics)
• alpha-Synuclein (genetics)