The long-term goal of this research program is to understand the biochemical pathways that regulate age-dependent neuronal viability in metazoans. Using a tractable genetic system to elucidate these pathways and uncover the mechanisms by which they contribute to neurodegenerative diseases and normal senescence, are important goals of my research. We have isolated a number of mutants in an unbiased forward genetic screen that provide us a novel perspective with which to study neuronal senescence and neurodegeneration in vivo. This proposal focuses on mutations that affect ATPalpha (Na/K ATPase), which cause progressive neurodegeneration in Drosophila. In humans loss-of-function Na/K ATPase mutations cause Rapid-onset Dystonia Parkinsonism (RDP) and familiar hemiplegic migraines (FHM). Na/K ATPase activity is reduced after ischemia and traumatic brain injury, and is associated with Alzheimer's disease. We hypothesize that neuropathogenesis is mechanistically similar in our mutants and patients with neurological diseases, including RDP and FHM, and propose experiments to elucidate these mechanistic details. Additionally, we propose to identify mutations capable of suppressing the underlying dysfunction and neurodegeneration. We will study these mutants using genetic, molecular, cell biological, and biochemical techniques to elucidate the mechanisms by which the mutations lead to cellular dysfunction and discover how this dysfunction manifests as neurological phenotypes, such as paralysis, seizures and progressive neurodegeneration. Together these specific experiments will elucidate the mechanisms of neuropathogenesis in ATPalpha mutants and lead to a better understanding of age-related neurodegeneration and senescence. ? ? ?
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