Neurotrophin Therapy of Neurodegenerative Disorders with Mitochondrial Dysfunction; Annual rept. 1 Sep 2006-31 Aug 2007

摘要

This research program will determine whether accelerated neuron death due to increased oxidative stress resulting from mitochondrial dysfunction can be compensated or corrected by neurotrophin stimulation. The experiments will be carried out in two models of mitochondrial dysfunction: (1) Hippocampal neurons from the trisomy 16 mouse, which undergo increased apoptosis and have a mitochondrial defect, that has now been identified as a decrease in Complex I-mediated respiration and altered mitochondrial protein expression; and (2) neurons chronically treated with the neurotoxin rotenone to induce a defect in mitochondrial function. 0.1-0.5 nM rotenone treatment has now been shown to leave hippocampal neurons vulnerable to a second oxidative stress. A unique aspect of this approach is that the neuronal responsiveness to brain derived neurotrophic factor (BDNF) will be enhanced by breeding to a mouse line with altered BDNF receptor expression. Neurons with an enhanced response to endogenous BDNF may be more resistant to oxidative stress characteristic of Parkinson's disease and other neurodegenerative disorders.