Neurons require release of critical signaling molecules known as neurotrophins from their target neurons for survival and normal function. Disruptions in this pathway are thought to be a risk factor in diseases like Alzheimer's, depression, and bipolar disease. Although the regulated secretion of neurotrophins is critical to the development and maintenance of neurons, we do not fully understand how the secretory granules needed to deliver neurotrophins are generated or delivered to where they are needed. A better understanding of this process will illuminate the normal functioning of the neuron and may reveal important insights in how these pathways contribute to Alzheimer's and affective disorders. We know that critical steps involved in the generation secretory granules like those needed for neurotrophin storage are of ancient evolutionary origin, so we can use the powerful genetic tools and methods of analysis to identify and analyze these steps in a single- celled organism, Tetrahymena. We can then use the information gained in Tetrahymena to define essential mammalian homologues involved in neurotrophin storage. Our approach will be to exploit specific features of Tetrahymena in combination with next-generation whole genome sequencing, to identify the genetic lesions that underlie a set of mutants with defects in secretory granule formation. PUBLIC HEALTH RELEVANCE: Alzheimer's disease represents an enormous and growing public health problem, whose etiology is still poorly understood. One contributing factor appears to be the storage and release from nerve cells of signaling molecules called neurotrophins. By studying a similar pathway in a single-celled organism, we can identify key genes that are required for neurotrophin storage, and thereby help to understand how defects in this pathway can lead to disease.