The Molecular Genetics of Age-Related Neurodegeneration in the Eye of Drosophila
Our overall objective is to use the common fruit fly, Drosophila as a model for studying hereditary human neurodegenerative diseases. We use the Drosophila eye as a model for understanding the molecular genetic basis of neurodegeneration. We are focused on the processes of protein trafficking and targeting with the goal of uncovering the mechanisms of neuropathology and cell death. We use Drosophila to understand neurodegenerative diseases such as Alzheimer's disease, Parkinson's, ALS, Huntington's, retinitis pigmentosa (RP) and age-related macular degeneration (AMD). An ongoing challenge in diagnosing and treating many of these disorders is that they are highly complex diseases with multiple subtypes and many distinct genetic and biochemical defects. This complexity, together with the broad base of knowledge of Drosophila genetics, all combine to make Drosophila a powerful animal model for studying inherited neurodegeneration disorders. Genes in Drosophila are highly conserved in humans. These similarities are not only within protein amino acid sequences but also within signaling pathways within cells. Therefore, our studies in Drosophila are providing insights into the underlying basis of neuodegeneration and approaches for therapeutic treatments.
We are interested in the genetic and molecular basis of protein trafficking and targeting within cells. We are focused on those events in the secretory pathway that ensure the proper folding, modification, oligomeric assembly, quality control, transport and targeting of newly synthesized proteins. During biosynthesis, proteins are synthesized in the endoplasmic reticulum (ER) and transported through the secretory pathway to their final destination within the cell. Within the ER, they are folded, assembled, and modified with carbohydrates. The ER contains a wide variety of molecular chaperones, folding sensors, enzymes, and escort proteins that facilitate these early stages of protein biosynthesis.
We study the genetic basis of neurodegenerative disorders resulting from mutations that cause protein misfolding, aggregation, and accumulation in inappropriate locations in the cell. Molecular chaperones not only play an essential role in ensuring proper protein folding, targeting and transport, but also promote the refolding of proteins that have become misfolded due to mutations and cellular stress. Therefore, molecular chaperones can be the first line of defense against misfolded proteins and are known to be potent supressors of neurodegeneration. Since genes and signaling pathways are conserved, our studies in Drosophila are providing insights into the underlying basis of neuodegeneration and therapeutic approaches for treatment.
See an article about Professor Colley's work in the IOA newsletter, entitled "Possible Key to Blindness & Other Degenerative Nerve Diseases," Aging News, 2012, Spring/Summer, see pages 4-5.
Colley, N. J., & Nilsson, D. E. (2016). Photoreception in phytoplankton. Integrative and Comparative Biology, 56(5), 764-775.
View publication via DOI: DOI:10.1093/icb/icw037
Nilsson, D. E., & Colley, N. J. (2016). Comparative vision: Can bacteria really see? Current Biology, 26(9), R369-371.
View publication via DOI: DOI:10.1016/j.cub.2016.03.025
Rosenbaum, E. E., Vasiljevic, E., Brehm, K. S., & Colley, N. J. (2014). Mutations in four glycosyl hydrolases reveal a highly coordinated pathway for rhodopsin biosynthesis and N-glycan trimming in Drosophila melanogaster. PLoS Genetics, 10(5), e1004349.
View publication via DOI: DOI:10.1371/journal.pgen.1004349
Rosenbaum, E. E., Vasiljevic, E., Cleland, S. C., Flores, C., & Colley, N. J. (2014). The Gos28 snare protein mediates intra-Golgi transport of rhodopsin and is required for photoreceptor survival. The Journal of Biological Chemistry, 289(47), 32392-32409.
View publication via DOI: DOI:10.1074/jbc.M114.585166
Colley, N. J., & Dowling, J. E. (2013). Spotlight on the evolution of vision. Visual Neuroscience, 30(1-2), 1-3.
View publication via DOI: DOI:10.1017/S0952523813000059
Colley, N. J. (2012). Retinal Degeneration in the Fly. Advances in Experimental Medicine and Biology, 723, 407-14.
View publication via DOI: DOI:10.1007/978-1-4614-0631-0_52
Rosenbaum, E.E., Brehm, K.S Vasiljevic, E., Gajeski, A., & Colley, N.J. (2012). Drosophila GPI-mannosyltransferase 2 is Required for the GPI Attachment and Surface Expression of Chaoptin. Visual Neuroscience. 29(3), 143-156.
View publication via DOI: DOI:10.1017/S0952523812000181
Weiss, S., Kohn, E., Dadon, D., Katz, B., Lebandiker, M., Kosloff, M., Colley, N. J., & Minke, B. (2012). Compartmentalization and Ca2+ buffering are essential for prevention of light induced retinal degeneration. Journal of Neuroscience, 32(42),14696-14708.
View publication via DOI: DOI:10.1523/JNEUROSCI.2456-12.2012
Rosenbaum, E.E., Brehm, K. S., Vasiljevic, E., Liu, C.-H., Hardie, R.C. & Colley, N.J. (2011). XPORT-Dependent Transport of TRP and Rhodopsin. Neuron, 72(4), 602-15.
View publication via DOI: DOI:10.1016/j.neuron.2011.09.016
Colley, N. J. (2010). Retinal degeneration through the eye of the fly. In D. A. Dartt (Ed.), Encyclopedia of the eye (Vol. 4, pp. 54-61). Oxford: Academic Press.
Kraus, A., Jung. J., Groenendyk, J., Bedard, K., Krause, K. H., Dubois-Dauphin, M., Baldwin, T. A., Agellon, L. B., Dyck, J., Gosgnach, S., Rosenbaum, E. E., Korngut, L., Colley, N. J., Zochodne, D., Todd, K., & Michalak, M. (2010). Calnexin deficiency leads to dysmyelination. Journal of Biological Chemistry, 285, 18928-18938.
View publication via DOI: DOI:10.1074/jbc.M110.107201 jbc.M110.107201
Tong, D., N.S. Rozas, T. H. Oakley, J. Mitchell, Colley, N. J., & McFall-Ngai, M. J. (2009). Evidence for light perception in a bioluminescent organ. PNAS, 106, 9836-41.
View publication via DOI: DOI:10.1073/pnas.0904571106
Rosenbaum, E. E., Hardie, R. C., & Colley, N. J. (2006). Calnexin is essential for rhodopsin maturation, Ca2+
regulation, and photoreceptor cell survival. Neuron. 49(2), 229-241.
View publication via DOI: DOI:10.1016/j.neuron.2005.12.011
LaLonde, M. M., Janssens, H., Rosenbaum, E. E., Choi, S. Y., Gergen, J. P., Colley, N. J., Stark, W. S., & Frohman, M. A. (2005). Regulation of phototransduction responsiveness and retinal degeneration by a phospholipase D-generated signaling lipid. The Journal of Cell Biology, 169(3), 471-479.
View publication via DOI: DOI:10.1083/jcb.200502122
Cohen, J. H., Piatigorsky, J., Ding, L., Colley, N. J. , Ward, R., & Horwitz, J. (2005). Vertebrate-like βγ-crystallins in the ocular lenses of a copepod. Journal of Comparative Physiology. A, Sensory, Neural, and Behavioral Physiology. 191(3), 291-298.
View publication via DOI: DOI:10.1007/s00359-007-0221-2
Winkfein, R. J., Pearson, B., Ward, R., Szerencsei, R. T., Colley, N. J., & Schnetkamp, P. P. M. (2004). Molecular characterization, functional expression and tissue distribution of a second NCKX Na+
exchanger from Drosophila
. Cell Calcium, 36(2), 147-155.
View publication via DOI: DOI:10.1016/j.ceca.2004.01.021
Webel, R., Haug-Collet, K., Pearson, B., Szerencsei, R. T., Winkfein, R. J., Schnetkamp, P. P. M., & Colley, N. J. (2002). Potassium-dependent sodium-calcium exchange through the eye of the fly. Ann NY Acad Sci., 976(1), 300-314.
View publication via DOI: DOI:10.1111/j.1749-6632.2002.tb04753.x
Mollereau, B., Dominguez, M., Webel, R., Colley, N. J., Keung, B., de Celis, J. F., & Desplan, C. (2001). Two-step process for photoreceptor formation in Drosophila
. Nature, 412(6850), 911-913.
View publication via DOI: DOI:10.1038/35091076
Hartman, S. J., Menon, I., Haug-Collet, K., & Colley, N. J. (2001). Expression of Rhodopsin and arrestin during the light-dark cycle in Drosophila
. Molecular Vision, 7, 95-100.
Colley, N. J. (2000). Actin' up with Rac1. Science, 290(5498), 1902-1903.
View publication via DOI: DOI:10.1126/science.290.5498.1902
Webel, R., Menon, I., O'Tousa, J., & Colley, N. J. (2000). Role of asparagine-linked glycosylation sites in Rhodopsin maturation and association with its molecular chaperone, NinaA. Journal of Biological Chemistry, 275(32), 24752-24759.
View publication via DOI: DOI:10.1074/jbc.M002668200
Raghu, P., Colley, N. J., Webel, R., James, T., Hasan, G., Danin, M., Selinger, Z., & Hardie, R. C. (2000). Normal phototransduction in Drosophila
photoreceptors lacking an InsP3
receptor gene. Molecular and Cellular Neuroscience, 15(5), 429-445.
View publication via DOI: DOI:10.1006/mcne.2000.0846
Haug-Collet, K., Pearson, B., Webel, R., Szerencsei, R. T., Winkfein, R. J., Schnetkamp, P. P. M., & Colley, N. J. (1999). Cloning and characterization of a potassium-dependent sodium/calcium exchanger in Drosophila
. Journal of Cell Biology, 147(3), 659-669.
View publication via DOI: DOI:10.1083/jcb.147.3.659
Sturtevant, M. A., Roark, M., O'Neill, J. W., Biehs, B., Colley, N. J., & Bier, E. (1996). The Drosophila
rhomboid protein is concentrated in patches at the apical cell surface. Developmental Biology, 174(2), 298-309.
View publication via DOI: DOI:10.1006/dbio.1996.0075
Colley, N. J., Cassill, J. A., Baker, E. K., & Zuker, C. S. (1995). Defective intracellular transport is the molecular basis of rhodopsin-dependent dominant retinal degeneration. Proceedings of the National Academy of Sciences of the United States of America, 92(7), 3070-3074.
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