My laboratory seeks to understand how neurons regulate their survival. Our specific goal is to determine the mechanism of activation of photoreceptor cell death in response to putative misfolding mutants of opsin. In the past year, we have discovered that the hid gene is required for neurodegeneration in this animal model of retinitis pigmentosa. To our knowledge, this is the first example of the involvement of an RHG-motif protein in a neurodegenerative process, and the second example of functional rescue of a cell by blocking apoptosis. We have submitted the findings to Nature Neuroscience. We also discovered that photoreceptor cell death in this system is induced by the combined action of light-dependent and independent pathways. One project in the lab is now focused on distinguishing the molecular players in the two pathways. Using the techniques of genetics, molecular biology and cell biology, we are testing the prevailing hypotheses concerning the role of rhodopsin and mutant opsin in apoptosis. We found that the opsin mutations that induce adult photoreceptor cell death in a light-dependent manner have at least partial survival signaling function during development. This has led us to re-evaluate the hypothesis that the mutants are toxic gain-of-function proteins. Our current aim in this project is to distinguish whether cell death is actually caused by the loss of wild type opsin, or a combination of the two mechanisms. The answer to this question will influence the design and interpretation of research into the molecular signaling pathways, as well as putative anti-apoptotic therapies. In order to identify novel genes that regulate the activation of cell death, we have initiated a major genetic screen for enhancers and suppressors of degeneration in mutant-opsin expressing photoreceptor neurons. The initial screen is expected to be completed in several more months. In addition to this unbiased, forward-genetics approach, we are testing mutations in candidate genes that we suspect to be involved in the degenerative process. Included in these is the Drosophila homolog of TRAF4, which we determined to have a role in both neurogenesis and myogenesis. A manuscript describing these results was submitted to Molecular Cell.
