Bioenergetic Defects and Oxidative Damage in Transgenic Mouse Models of Neurodegenerative Disorders

摘要

The initial three years of this project determined the contributions of bioenergetic defects and oxidative stress to neurodegeneration in Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). A Consortium project, 'Mitochondrial Free Radical Generation in Parkinson's Disease', was then incorporated into the grant award (2 years), to assess in vivo whether mitochondria are the source of free radical generation in animal models of Parkinson's disease (PD). Studies in the original grant period generated several novel observations of presymptomatic energetic abnormalities in mouse genetic models of both HD (R6/2, N171-82Q, Hdh Q50, 92, 111 mice) and ALS (G93A mice). Specifically, in vivo studies showed that glucose uptake is non- specifically elevated throughout the forebrain in two HD mouse models (N171-82Q and HdhQlll and Q92) before symptom onset, and that ATP defects and oxidative damage precede symptom onset in some models. In ALS mice, in contrast glucose use is reduced in discrete motor pathways in brain, preceding changes in spinal cord. Studies examining the relationship between mitochondrial complex I inhibition and free radical-mediated oxidative damage in rat neurotoxin models (rotenone and pyridaben) demonstrate increased oxidative damage rapidly after complex I inhibition (including lipid peroxidation and induction of the stress- response marker heme oxygenase-1).