Genome-wide microarray analysis of the differential neuroprotective effects of antioxidants in neuroblastoma cells overexpressing the familial Parkinson's disease alpha-synuclein A53T mutation.
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.
Ma
Lei
L
WP Alzheimer's, Merck Research Laboratories, P.O. Box 4, WP26A-2000, West Point, PA 19486-0004, USA. lei_ma@merck.com
Cao
Tracy T
TT
Kandpal
Geeta
G
Warren
Lee
L
Fred Hess
J
J
Seabrook
Guy R
GR
Ray
William J
WJ
D000975:Antioxidants / Q000378:metabolism*; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D017931:DNA Primers; D016678:Genome; D006801:Humans; D009154:Mutation; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010300:Parkinson Disease / Q000235:genetics*; D051844:alpha-Synuclein / Q000235:genetics*
D000975:Antioxidants; D017931:DNA Primers; D051844:alpha-Synuclein