Mitochondrial dysfunction by oxidative damage

Sylvette Ayala-Torres, Ph.D.

Mitochondria are the principal sources of endogenous reactive oxygen species (ROS) (1). Mitochondria have their own DNA (mtDNA), which is a clear target for ROS-induced damage (2). Many forms of neurodegeneration are associated with oxidative stress including Huntington’s disease (HD), which is characterized by the degeneration of the striatal and cerebral cortex neurons (3,4). Moreover, mitochondrial dysfunction and oxidative damage to DNA have been suggested to play a role in HD (5,6). However, the cause of the differential neurodegeneration observed in HD remains unclear. We want to test the hypothesis that damage to mtDNA plays a role in the pathology observed in HD. In order to test this hypothesis, we have employed a transgenic mouse model of HD (R6/2) which about 6 weeks of age, they develop loss of brain and body weight, and at about 9 weeks they develop an irregular gait, abrupt shuttering, resting tremors, epileptic seizures, and premature death between 10-13 weeks (7). Several clinical and pathological features have been shown to occur in both the R6/2 HD mouse model and post-mortem brains of patients with HD (7). Therefore, the R6/2 mice represent a good HD mouse model to study the molecular and biochemical events acting in HD pathogenesis.  The results of our study show that cerebral cortex from HD transgenic mice of 10 and 12 weeks of age exhibit higher levels of mtDNA damage than the age-matched wild-type mice.  In addition, we found that hippocampus from HD transgenic mice of 12 weeks of age exhibit higher levels of mtDNA damage than the age-matched wild-type mice.  These results suggest that mtDNA damage may play role in the pathogenesis of HD in the R6/2 transgenic mouse model of HD.  Future work in this project will be focused at augmenting the natural antioxidant systems of the R6/2 mice by the administration of superoxide dismutase and catalase mimetics, synthetic compounds known to mimic the activity of the antioxidant enzymes superoxide dismutase and catalase and to ameliorate oxidative stress in various disease models (8). We will examine the amounts of mtDNA damage in cerebral cortex, hippocampus and striatum, time of survival, loss of body weight, and the behavioral outcome of the R6/2 mouse model of HD after administration of the antioxidant enzymes mimetics.  The RCMI Behavioral Testing Facilities housed at UCC will be absolutely necessary to perform the behavioral studies.

References:

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2. F.M. Yakes and B. Van Houten (1997) Mitochodrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc. Natl. Acad. Sci. USA 94:514-519
3. Bogdanov, M.B., Ferrante, R.J., Kuemmerle, S., Klivenyi, P., and Beal, M.F. (1998) Increased vulnerability to 3-nitropropionic acid in an animal model of Huntington’s disease. J. Neurochem. 71:2642-2644.
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5. M. C. Polidori et al. (1999) Oxidative damage to mitochondrial DNA in Huntington’s disease parietal cortex. Neuroscience Letters 272:53-56
6. S. J. Tabrizi et al. (2000) Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse. Ann. Neurol. 47:80-86
7. L. Mangiarini et al. (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87: 493-506
8. Melov, S. et al., (2000) Extension of life-span with superoxide dismutase/catalase mimetics. Science 289:1567-1569