Bioenergetic Defects and Oxidative Damage in Transgenic Mouse Models of Neurodegenerative Disorders
Abstract
This project aimed to determine the contributions of bioenergetic dysfunction and oxidative stress to neurodegeneration in Huntington's disease (HE)) and amyotrophic lateral sclerosis (ALS). We found elevations in cerebral glucose utilization in two distinctly different mutant mouse models of HD: Hdh(Q92) and N171-82Q. Hypermetabolism preceded pathologic changes and symptoms, but was not accompanied by alterations in oxidative phosphorylation enzyme activities. We also found late increases in oxidative damage to DNA -and lipids in R6/2 and N171-82Q HD mice. Another approach to model HD is to inhibit mitochondrial complex II using the neurotoxin 3-nitropropionic acid (3-NP). In contrast to genetic models, reductions in glucose use following 3- NP coincided with neuronal loss, suggesting a different sequence of pathologic events in this model. In a model of ALS, G93A mice, we also found early metabolic changes preceding neuronal pathology and symptom onset. Reduced glucose utilization in brain and spinal cord at 60 days of age was concomitant with increased mitochondrial complex I activity and depletions in ATP levels. Elevated free radical generation was evident by 90 days. Results clearly demonstrate the early involvement of metabolic changes in the pathologic events initiated by expression of the mutant disease gene in ALS and HD models.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2002
- Accession Number
- ADA408717
Entities
People
- Susan E. Brown
Organizations
- Weill Cornell Medicine