Patrick J. Dolph
Associate Professor of Biological Sciences
Research Areas: Signal Transduction and Cellular Metabolism
Retinal and Neuronal Degeneration in Drosophila
Inherited retinal degeneration leads to vision loss in hundreds of thousands of people each year. Although mutations in specific genes have been identified that are responsible for retinal disease, the molecular mechanism responsible for the photoreceptor cell degeneration is unknown in nearly all cases. Our laboratory uses the fruit fly Drosophila melanogaster as a model system to study retinal degeneration.
Invertebrate photoreceptors respond to light via a G protein-coupled receptor/phosphatidylinositol signaling cascade. This visual transduction cascade is shut off, in part, by the binding of arrestin to the light receptor rhodopsin. We have found that in several different mutants that undergo retinal degeneration, this transient interaction between rhodopsin and arrestin is stabilized. The resulting rhodopsin/arrestin complexes are internalized into the cell body by receptor-mediated endocytosis. Once internalized, rhodopsin accumulates in specific intracellular compartments and induces cell death of the photoreceptor cells. Presently, we are using genetic, biochemical, and molecular techniques to dissect this cell death pathway and understand how the accumulation of these protein complexes in the cell body induces photoreceptor death.
We have also established a Drosophila model for prion disease. Expression of a pathogenic form of PrP protein in a subset of Drosophila neurons results in altered mobility of adult animals and reduced lifespan. In addition, we find an intracellular accumulation of misfolded PrP and neuronal degeneration. We are presently using the powerful genetic tools of Drosophila to isolate modifiers of these phenotypes in an effort to understand the molecular basis of neuronal degeneration in prion disease.
Publications
Dasgupta, U., Bamba, T., Chiantia, S., Karim, P., Tayoun, A.N., Yonamine, I., Rawat, S.S., Rao, R.P., Nagashima, K., Fukusaki, E., Puri, V., Dolph, P.J., Schwille, P., Acharya, J.K., and Acharya, U. 2009. Ceramide kinase regulates phospholipase C and phosphatidylinositol 4, 5, bisphosphate in phototransduction. Proc. Natl. Acad. Sci. USA. Nov 24;106(47):20063-8.
Bass, B.P., Tanner, E.A., Mateos San Martín, D., Blute, T., Kinser R.D., Dolph, P.J., and McCall, K. 2009. Cell-autonomous requirement for DNaseII in nonapoptotic cell death. Cell Death Differ. Oct;16(10):1362-71.
Chinchore, Y., Mitra, A., and Dolph, P.J. 2009. Accumulation of rhodopsin in late endosomes triggers photoreceptor cell degeneration. PLoS Genet. Feb;5(2):e1000377.
Gavin, B.A., Arruda, S.E., and Dolph, P.J 2007 The role of carcinine in signaling at the Drosophila photoreceptor synapse. PLoS Genetics Dec;3(12): e206
Gavin, B.A., Dolph, M.J., Deleault, N.R., Geoghegan, J.C., Khurana, V., Feany, M.B., Dolph, P.J., and Supattapone, S. 2006 Accelerated accumulation of misfolded prion protein and spongiform degeneration in a Drosophila model of Gerstmann-Str"aussler-Scheinker syndrome. J. Neurosci. Nov 29;26(48):12408-14.
Orem, N.R., Xia, L., and Dolph, P.J. 2006 An essential role for endocytosis of rhodopsin through interaction of visual arrestin with the AP-2 adaptor. J. Cell Sci. Aug 1;119(Pt 15):3141-8.
Arruda, S.E., and Dolph, P.J. 2003 Molecular cloning of the pawn locus from Drosophila melanogaster. Gene. May 22;310:169-73.
Deleault, N.R., Dolph, P.J., Feany, M.B., Cook, M.E., Nishina, K., Harris, D.A., and Supattapone, S. 2003 Post-transcriptional suppression of pathogenic prion protein expression in Drosophila neurons. J. Neurochem. Jun;85(6):1614-23.