In vivo selection for gene mutations that counteract photoreceptor degeneration

Diseases involving death of nerves in the brain are a major health problem. Some, such as Alzheimer disease and age related macular degeneration, are increasingly common among the United States population. The nerves affected vary among disorders and the underlying causes are likely diverse as well. Effective treatments have been slow in coming, despite much effort. Numerous disease models exist in which animals are born with a normal complement of nerves, but particular types of nerves degenerate over time. We hypothesize that mutations in yet to be determined genes can increase the survival of fatally flawed nerves. We propose to identify such genes by mutating a large group of nerves that is destined to die, letting the degeneration process progress, and then assessing which mutations are present in the surviving nerves. We will pilot our method on the light sensing nerves of the eye. Success of this seed project will motivate extension of our approach to animal models that affect other types of nerves in the brain. Comparison of survival-promoting genes among different types of nerves dying due to a variety of underlying causes would be revelatory. Moreover, the genes/proteins we identify will be excellent targets for therapy development.