The goal of the proposed research is to explore the potential role of monoamine oxidase B (MAO-B) in neuronal degeneration associated both with normal aging and in neurodegenerative disorders such as Parkinson's and Alzheimer's disease. It has been hypothesized that due to its age-related increase in the brain coupled with its ability to produce reactive oxygen species (ROS) as a by-product of its enzymatic action, MAO-B could contribute to age-related neurodegeneration by eliciting increased oxidative stress and mitochondrial damage either on its own or possibly through its interaction with either endogenous and exogenous neurotoxic species. We plan to directly explore this hypothesis by creating genetically engineered PC12 cell lines with increased levels of MAO-B and transgenic animals in which levels of glial MAO-B can be inducibly increased in the adult animal. These models will be tested for effects of increased MAO-B activity on mitochondrial function and generation of oxidative stress in both the absence and presence of the Parkinsonian-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). The effect of elevation of brain MAO-B on microanatomical glial and neuronal changes associated with aging will also be assessed in adult animals. The transgenic lines proposed are superior to existing MAO-B transgenic lines previously created by ourselves in which MAO-B levels are altered not only in the adult but throughout development. Genetically controlled inducible delivery of the enzyme is more precise for examining the effects of MAO-B elevation in the adult and furthermore can be examined in a genetically homogeneous background in transgenic mouse lines, something that is often not possible in human studies. This work will complement on-going work in the laboratory exploring the role of free radicals in neurodegeneration during both aging and in neurodegenerative disease using mice with variant brain expression of molecules that are believed to be protective against free-radical damage including ferritin and glutathione/glutathione peroxidase.
|Kumar, M Jyothi; Nicholls, David G; Andersen, Julie K (2003) Oxidative alpha-ketoglutarate dehydrogenase inhibition via subtle elevations in monoamine oxidase B levels results in loss of spare respiratory capacity: implications for Parkinson's disease. J Biol Chem 278:46432-9|