Our aim is to understand the control of neuronal cell death. We study this in terminally differentiated photoreceptor neurons (PRNs) of the retina. Our studies utilize Drosophila, where PRNs degenerate and die in response to some of the same stimuli that cause blindness in humans. We expect these studies to yield insight into mechanisms and possible therapies for a variety of chronic diseases, including cancer and degenerative CNS disorders.Our studies have elucidated environmental, genetic, and epigenetic factors controlling PRN degeneration and death. These include light, cell-death-regulatory genes such as hid, TRAF, caspases and dIAP1, and the ras mitogen-activated kinase pathway genes. Where investigated, we found that suppression of degeneration resulted in preservation of visual function, underscoring our earlier finding that degeneration is the cause, rather than consequence, of loss of PRN function. By genetic screening, we have identified additional suppressor and enhancer loci; a current aim is to pinpoint the genes responsible. A related aim is to incorporate genomics to accelerate the pace of gene discovery. Pilot experiments indicate the feasibility of this approach. In addition, we have discovered an apparent correlation between picornaviral infection and the age of onset of PRN degeneration. This suggests a potentially significant factor in the well-known variability of neurodegenerative phenotypes in different individuals. Experiments are underway to confirm the identity of this putative viral trigger.Additional areas of research include ultrastructural analyses of the connection between PRN degeneration and death, studies of the role of native rhodopsin in cell viability, and generation of transgenic constructs for probing the biochemistry of degeneration. Highlights include the finding that rhodopsin mutations causing degeneration in humans and flies are partial-loss-of-function mutations, rather than toxic-gain-of-function as previously believed. This reframes the mechanistic questions from """"""""How do misfolded rhodopsins kill cells?"""""""" to """"""""How does wild type rhodopsin keep cells alive?"""""""" Given the membership of rhodopsin in the GPCR family of proteins, these results are consistent with emerging evidence of a regulatory role for GPCRs in normal cell death regulation. Elucidating the molecular links between native rhodopsin function and PRN integrity/viability will thus be a major future focus.
