This proposal describes the first steps in understanding the genetic, molecular and cellular basis of one model of age-dependent behavioral and neural degeneration. This has become highly relevant to human health and quality of life as advanced medicine now allows many people to survive for years with significant behavioral and cognitive deficits. The entree into these studies is the recent observation that mutations in the Drosophila kelch gene lead to age-dependent deficits in mating success, sexual receptivity, and body control without significantly reduced viability. The relevance of these studies is increased by the identification of nervous-system-expressed homologs of kelch in humans. The long term goal of this project is to understand the cellular basis of neural and behavioral defects associated with kelch mutations, to link this to the molecular action of Kelch, to use appropriate manipulations of kelch mutations to screen for addition proteins interacting with Kelch in maintenance of neural function, and to model the potential action of wild type and mutant versions of the human Kelch-like proteins. In this pilot project special emphasis will be given to laying the necessary foundation for the more ambitious long term goals. Molecularly mapped nonsense and missense mutations will be carefully characterized for severity and time course of multiple behavioral phenotypes. This will determine the array of possible kelch phenotypes and the consequences of alterations in defined protein domains. In parallel with the characterization of age- dependent behavioral phenotypes, age-associated abnormalities in the CNS, neuromuscular system, and visual system will be examined, both in the CNS as a whole and in defined subsets of neurons or glia. Characterization of alterations in the CNS or peripheral nervous system will be correlated with expression patterns for Kelch as determined by RNA hybridization and Kelch-specific antibodies. Reagents for later studies, including targeted expression of Kelch, GFP-Kelch and corresponding human proteins in animals or in culture, and examination of small groups of Kelch mutant cells will be constructed.
| Finley, Kim D; Edeen, Philip T; Cumming, Robert C et al. (2003) blue cheese mutations define a novel, conserved gene involved in progressive neural degeneration. J Neurosci 23:1254-64 |
