Genomic and biochemical approaches in the discovery of mechanisms for selective neuronal vulnerability to oxidative stress
1 Higuchi Biosciences Center, 2099 Constant Ave., University of Kansas, Lawrence, KS 66047, USA
2 Department of Pharmacology and Toxicology, 1251 Wescoe Dr., University of Kansas, Lawrence, KS 66045, USA
3 Current address: Department of Biochemistry, 1750 Independence Ave., Kansas City University of Medicine and Biosciences, Kansas City, MO 64106, USA
4 Bioinformatics and Computational Life Sciences Laboratory, Department of Electrical Engineering and Computer Science, 2335 Irving Hill Rd., University of Kansas, Lawrence, KS 66045, USA
5 Current address: Stowers Institute for Medical Research, 1000 E 50th St., Kansas City, MO 64110, USA
6 Current address: Daiichi Sankyo Inc., Two Hilton Court, Parsippany, NJ 07054, USA
BMC Neuroscience 2009, 10:12 doi:10.1186/1471-2202-10-12Published: 19 February 2009
Oxidative stress (OS) is an important factor in brain aging and neurodegenerative diseases. Certain neurons in different brain regions exhibit selective vulnerability to OS. Currently little is known about the underlying mechanisms of this selective neuronal vulnerability. The purpose of this study was to identify endogenous factors that predispose vulnerable neurons to OS by employing genomic and biochemical approaches.
In this report, using in vitro neuronal cultures, ex vivo organotypic brain slice cultures and acute brain slice preparations, we established that cerebellar granule (CbG) and hippocampal CA1 neurons were significantly more sensitive to OS (induced by paraquat) than cerebral cortical and hippocampal CA3 neurons. To probe for intrinsic differences between in vivo vulnerable (CA1 and CbG) and resistant (CA3 and cerebral cortex) neurons under basal conditions, these neurons were collected by laser capture microdissection from freshly excised brain sections (no OS treatment), and then subjected to oligonucleotide microarray analysis. GeneChip-based transcriptomic analyses revealed that vulnerable neurons had higher expression of genes related to stress and immune response, and lower expression of energy generation and signal transduction genes in comparison with resistant neurons. Subsequent targeted biochemical analyses confirmed the lower energy levels (in the form of ATP) in primary CbG neurons compared with cortical neurons.
Low energy reserves and high intrinsic stress levels are two underlying factors for neuronal selective vulnerability to OS. These mechanisms can be targeted in the future for the protection of vulnerable neurons.