Oxidative stress has been hypothesized to be a major factor in the etiology of many progressive age related neurodegenerative diseases including Alzheimer and Parkinson disease, amytrophic lateral sclerosis, Friedreichs ataxia, and the prion diseases. The chief source of oxidative stress within the cell is the mitochondrion. The main ROS produced is the superoxide radical ( O'~) which under normal circumstances is reduced to H2O2 via the mitochondrial form of superoxide dismutase (Sod2). We have previously reported that inactivation of this gene results in neonatal lethality accompanied by a dilated cardiomyopathy, hepatic lipid accumulation, oxidative DNA damage, organic aciduria, spongiform encephalopathy, gliosis, and mitochondrial enyzmatic abnormalities. We have also demonstrated that many of these phenotypes can be ameliorated by synthetic antioxidant treatment. The long term goals of these studies are to 1) understand the molecular targets of mitochondrial oxidative stress both at the genetic and protein level within the brain, & 2) characterize the efficacy of synthetic antioxidants in preventing many of the CNS disorders which present due to mitochondrial oxidative stress within the brain.
The specific aims are 1) Characterize the metabolism of the affected areas of the brain to determine if there is a metabolic differential relative to unaffected areas; 2) Determine whether cell loss contributes to the progression of the spongiform changes; 3) Characterize at the biochemical and enzymatic level the changes due to mitochondrial oxidative stress within the brain and the efficacy of various synthetic antioxidants in attenuating such changes; 4) Investigate gene expression changes in the brain in relation to endogenous mitochondrial oxidative stress via microarray analysis. Experimental methods include; growth and harvesting of Sod2 mutant mice and controls with and without synthetic antioxidant treatment, histopathological analysis, stereological cell counting, metabolic measurements via 2-deoxyglucose labeling, biochemical analysis of mitochondria from control and experimental groups, and microarray analysis of RNA from control and experimental groups of both affected and unaffected areas.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG018679-02
Application #
6372535
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Wise, Bradley C
Project Start
2000-08-15
Project End
2005-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
2
Fiscal Year
2001
Total Cost
$329,000
Indirect Cost
Name
Buck Institute for Age Research
Department
Type
DUNS #
800772162
City
Novato
State
CA
Country
United States
Zip Code
94945
Velarde, Michael C; Demaria, Marco; Melov, Simon et al. (2015) Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells. Proc Natl Acad Sci U S A 112:10407-12
Campisi, Judith; Andersen, Julie K; Kapahi, Pankaj et al. (2011) Cellular senescence: a link between cancer and age-related degenerative disease? Semin Cancer Biol 21:354-9
Samper, Enrique; Morgado, Lucia; Estrada, Juan C et al. (2009) Increase in mitochondrial biogenesis, oxidative stress, and glycolysis in murine lymphomas. Free Radic Biol Med 46:387-96
Mahoney, D J; Safdar, A; Parise, G et al. (2008) Gene expression profiling in human skeletal muscle during recovery from eccentric exercise. Am J Physiol Regul Integr Comp Physiol 294:R1901-10
Melov, Simon; Adlard, Paul A; Morten, Karl et al. (2007) Mitochondrial oxidative stress causes hyperphosphorylation of tau. PLoS One 2:e536
Melov, Simon; Tarnopolsky, Mark A; Beckman, Kenneth et al. (2007) Resistance exercise reverses aging in human skeletal muscle. PLoS One 2:e465
Golden, Tamara R; Beckman, Kenneth B; Lee, Andreia H J et al. (2007) Dramatic age-related changes in nuclear and genome copy number in the nematode Caenorhabditis elegans. Aging Cell 6:179-88
Morten, Karl J; Ackrell, Brian A C; Melov, Simon (2006) Mitochondrial reactive oxygen species in mice lacking superoxide dismutase 2: attenuation via antioxidant treatment. J Biol Chem 281:3354-9
Xia, Xu-Gang; Zhou, Hongxia; Samper, Enrique et al. (2006) Pol II-expressed shRNA knocks down Sod2 gene expression and causes phenotypes of the gene knockout in mice. PLoS Genet 2:e10
Melov, Simon; Wolf, Norman; Strozyk, Dorothea et al. (2005) Mice transgenic for Alzheimer disease beta-amyloid develop lens cataracts that are rescued by antioxidant treatment. Free Radic Biol Med 38:258-61

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