This proposal is being submitted as an application for an AREA award that would allow the Principal Investigator to initiate a new research program related to aging and neurodegenerative diseases. As by-products of cellular respiration, a variety of oxygen reactive compounds are formed that can be highly damaging to most types of cellular macromolecules. Several degenerative disorders commonly associated with aging, including Alzheimer's and amyotrophic lateral sclerosis, are thought to involve oxidative damage. Studies using fruit flies (Drosophila melanogaster) indicate that the motor neurons are the most sensitive tissue for oxidative damage. Superoxide dismutases (SODs) are cellular enzymes that initiate a series of reactions that ultimately convert highly reactive superoxide radical to water. Flies having a mutation in the SOD1 gene exhibit hypersensitivity to oxidizing agents and have dramatically shortened life spans. However, genetically engineered flies that express the SOD1 gene at above normal levels actually have extended life spans - nearly 40% longer than normal flies. Thus, there appear to be oxidation-sensitive macromolecules within the motor neurons that play a central role in the aging process. Minimizing the oxidative environment of the neurons actually slows the aging process. SOD reacts with a wide variety of compounds and thus, it is unlikely that we could identify these putative target molecules within the motor neurons. In contrast, peptide methionine sulfoxide reductases (Msr) specifically act on methionine sulfoxide residues in proteins. Here we propose experiments that test our overarching hypothesis that the expression of two Msr genes directly affects the life span of the organism and its resistance to oxidative stress. When methionine residues within critical neuronal proteins are oxidized, biological function is compromised and the aging process accelerates. Data from the experiments in this proposal will be used to develop an R01 grant application to identify these target proteins. Identification of these critical proteins would be a major contribution to our understanding of aging and lend insight into therapeutic approaches for neurodegenerative diseases such Alzheimer's and amyotrophic lateral sclerosis. ? ?
