The long-term objective of this research project is to harness the power of Drosophila genetics to identify novel genes and molecular mechanisms involved in age-related diseases, such as Alzheimer's disease (AD) and age-related macular degeneration (AMD). The proposed project is specifically focused on protein folding, transport, and targeting and how defects in these highly regulated processes lead to age- related neurodegenerative pathology. A goal is to understand how aging influences the cellular environment and enhances the cytotoxic effects of protein accumulation. Aberrant protein processing and accumulation are the culprits in many neurodegenerative diseases in the eye and brain. In the eye, neurodegeneration leads to blinding disorders such as AMD. AMD is the leading cause of vision loss in people over the age of 55. In the brain, neurodegeneration leads to cognitive disorders such as AD. AD affects over 5 million people in the U.S. alone and is the most common form of dementia among older people. The bases of AMD and AD are not well understood and no cures are available. Although age is clearly the most important known risk factor, there is a strong genetic component and several factors are likely at play. This complexity and the broad base of knowledge in Drosophila genetics, combine to make Drosophila a powerful animal model for studying age-related disorders. The Drosophila life span is about 2 months, allowing one to follow the onset and progression of age-related degenerations in a short period of time. Drosophila mutants that undergo age-related retinal degeneration will be utilized to uncover diverse molecular signaling mechanisms that coordinate protein biosynthesis in photoreceptor cells. The proposed experiments will use an integrated strategy of genetic, biochemical, cell biological, molecular, and electrophysiological approaches. Aim 1 involves the characterization of a novel Golgi SNARE protein, Gos28, and its role in vesicular trafficking. Aim 2 involves the identification and characterization of additional loci that genetically interact with gos28, and are thus part of a shared molecular pathway for protein trafficking. Finally, aim 3 involves the investigation of therapeutic approaches for slowing the onset and progression of neurodegeneration. Relevance to Public Health: Studies proposed here, using the Drosophila eye as a model, will provide insights into the general mechanisms of protein misfolding and defective targeting in age-related diseases, such as Alzheimer's disease and age-related macular degeneration. The ultimate goal of this proposal is to understand the cytotoxic effects of protein accumulation and use this knowledge to develop treatments that slow down the onset and progression of age-related neurodegeneration.