Bioenergetic Defects and Oxidative Damage in Transgenic Mouse Models of Neurodegenerative Disorders.
Annual rept. 1 Oct 98-30 Sep 99
MASSACHUSETTS GENERAL HOSPITAL BOSTON
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This study aims to determine what roles bioenergetic dysfunction and oxidative stress play in the etiology of neurodegeneration in Huntingtons disease HE and familial amyotrophic lateral sclerosis FALS, using transgenic mouse models. Studies in this first year employed C-14-2-deoxyglucose in vivo autoradiography and spectrophotometric metabolic enzyme assays. In the Hdh knock-in mouse model of HD we found no significant differences in cerebral glucose utilization between normal wild type mice HdhQ7 and mutant mice expressing 50 polyglutamines HdhQ50 at 4 months of age a timepoint preceding pathologic changes. However, significant decreases in activities of the mitochondrial electron transport chain enzymes complexes I, II-III and IV were evident in cerebellum from HdhQ50 and HdhQ92 mice at this time point. In the G93A transgenic mouse model of FALS we found that cerebral glucose use is reduced in several forebrain regions at 60 days of age - a time point preceding the onset of the first pathological changes in these mice. In addition, complex I activity is increased in the forebrain of G93A mice at the same time point, consistent with the defect seen in FALS A4V patients with a SOD1 mutation. We have made significant progress towards the original goals of this proposal.
- Anatomy and Physiology
- Medicine and Medical Research