Professor, Department of Cell Biology,
Dean A. McGee Professor of Ophthalmology,
Adjunct Professor of Biochemistry & Molecular Biology
B.A.., Mathematics, Texas A & M University, College Station, Texas
M.S., Chemistry, Texas A & M University, College Station, Texas
Ph.D., Biochemistry, Texas A & M University, College Station, Texas
M.D., Baylor College of Medicine, Houston, Texas
American Association for the Advancement of Science
American Society for Cell Biology
American Society for Neurochemistry
Association for Research in Vision and Ophthalmology (ARVO)
FASEB (American Society for Biochemistry and Molecular Biology)
International Society for Eye Research
International Society for Neurochemistry
International Society for the Study of Fatty Acids and Lipids
Society for Neuroscience
We are studying signaling pathways and mechanisms in the retina that provide neuroprotection from light and mutational stresses that cause retinal degenerations. Several in vivo and in vitro approaches are used.
1). We made the unique observation that light activates the phosphoinositide signaling pathway through tyrosine phosphorylation of the insulin receptor, which leads to downstream activation of anti-apoptotic molecules, including Akt/PKB. It is our hypothesis that light capture by the visual pigment rhodopsin routinely activates this pathway, which provides daily protection for these important post-mitotic neurons. Experiments are designed to elucidate the various steps that occur between the capture of a photon by rhodopsin and the stabilization of mitochondria/inhibition of caspases, which are necessary for neuroprotection. A variety of cell biological, biochemical, and molecular biological techniques are utilized in these studies, including the use of transgenic mice that express Cre recombinase in photoreceptor cells under the control of an inducible promoter. This approach has allowed us to knock out specific genes expressing proteins known to be involved in neuroprotection/apoptosis, only in specific cells such as rod and cone photoreceptors.
2). Stargardt-3 macular dystrophy (STGD3) is a dominantly inherited juvenile macular degeneration that eventually leads to loss of vision. We have determined that the mutated gene in STGD3, identified by others as ELOVL4, is responsible for biosynthesis of very long chain polyunsaturated fatty acids (VLC-PUFA) in the retina and a few select tissues (brain, skin, testes). Although we now know the function of the enzyme, it still remains to be determined why photoreceptor cells die in STGD3 patients. The answer to this question is important because it will determine therapeutic strategy. There are at least three explanations for the retinal phenotype seen in STGD3 patients: 1) VLC-PUFAs are necessary for cell survival and their loss leads to cell death, 2) Loss of ER retention signal leads to mislocalization of the ELOVL4 protein, which causes a metabolic stress that ultimately kills the cell, and 3) Mislocalization of the ELOVL4 leads to production of a intermediate (a 3-keto fatty acid) that is toxic to the cell. We are actively testing these three possible causes of cell death.
Notable discoveries from Dr. Anderson's laboratory include: 1) First demonstration of the essentiality of omega-3 fatty acids in retinal function, 2) The role of the phosphoinositide cascade in phototransduction in the invertebrate retina, 3) The role of the insulin receptor/PI 3-kinase/Akt pathway in stress-induced retinal degenerations, 4) The role of oxidant stress in light-induced apoptosis of photoreceptor cells, and 5) The identification of the biosynthetic step catalyzed by the ELOVL4 protein, which is mutated in Stargardt-3 juvenile macular degeneration.
The ultimate goal of our research program is to elucidate the molecular mechanisms of retinal degenerations and to use this knowledge to provide medical therapy to patients that suffer from devastating blinding diseases such as age-related macular degeneration, retinitis pigmentosa, Usher Syndrome, and Stargardt Disease.
1. Rajala, A., Anderson, R.E., Ma, J-X., Al-Ubaidi, M.R., Lem, J., and Rajala, R.VS. (2007). G protein-coupled receptor rhodopsin regulates the phosphorylation of retinal insulin receptor. J. Biol. Chem. 282:9865-9873. PMID: 17272282
2. Li, G., Rajala, A., Dilly, A.K., Wiechmann, A.F., Anderson, R.E., and Rajala, R.V.S. (2008). Light-dependent generation of phosphoinositides regulates the activation and membrane binding of retinal PKBα/Akt1. J Neurochem. 107:1382-1397. PMID: 18823366, PMC2596869
3. Agbaga, M.-P., Brush, R.S., Mandal, M.N.A., Henry, K., Elliott, M.H., and Anderson, R.E. (2008) Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids. Proc. Natl. Acad. Sci. USA 105:12843-12848. PMID: 18728184, PMC2525561
4. Tanito, M., Elliott, M.H., Brush, R.S., Wicker, L.D., Henry, K.R., and Anderson, R.E. (2009). High levels of retinal membrane DHA increase susceptibility to stress-induced degeneration. J. Lipid Res. 50:807-19 Nov 20. [Epub ahead of print]. PMID: 19023138, PMC2666167
5. Roqueta-Rivera, M., Stroud, C.K., Haschek, W.M., Akare, S.J., Segre, M., Brush, R.S., Agbaga, M-P., Anderson, R.E., Hess, R.A., and Nakamura, M.T. (2010). Docosahexaenoic acid supplementation fully restores fertility and spermatogenesis in male delta-6 desaturase knockout mice. J. Lipid Res. 51:360-367. PMC2803238
6. Rajala, R.VS. and Anderson, R.E. (2010). Rhodopsin-regulated insulin receptor signaling pathway in rod photoreceptor neurons. Molec. Neurobiol. 42:39-47, Apr 21. [Epub ahead of print]. PMC2962609
7. Agbaga, M.-P., Mandal, M.N.A., and Anderson, R.E. (2010). Retinal very long chain polyunsaturated fatty acids: new insights from studies on ELOVL4 protein. J. Lipid Res, 51:1624-42, Mar 18. [Epub ahead of print]. PMC2882734
8. Ivanovic, I., Anderson, R.E., Le, Y.Z., Fliesler, S.J., Sherry, D.M., and Rajala, R.V.S. (2011). Deletion of the p85α regulatory subunit of phosphoinositide 3-kinase in cone photoreceptor cells results in cone photoreceptor degeneration. Invest Ophthalmol Vis Sci, 52:3775-3783; published ahead of print March 11, 2011, doi:10.1167/iovs.10-7139. PMC3109053
9. Mandal, Md N.A., Moiseyev, G.P., Elliott, M.H., Kasus-Jacobi, A., Li, X., Chen, H., Zheng, L., Nikolaeva, O., Floyd, R.A, Ma, J-x., Anderson, R.E. (2011). PBN (α-phenyl-N-tert-butyl nitrone) prevents light-induced degeneration of the retina by Inhibiting RPE65 isomerohydrolase activity. J. Biol. Chem. 286:32491-32501, First Published on July 24, 2011, doi: 10.1074/jbc.M111.255877. PMC3173208
10. Rajala A, Dighe R, Agbaga, M-P, Anderson RE, Rajala RVS. (2013). Insulin receptor signaling in cones. J Biol Chem, 288:19503-19515. May 14. [Epub ahead of print]
11. Logan S, Agbaga, M-P, Chan, M.D., Kabir, N, Mandal, N.A., Brush, R.S., Anderson, R.E. (2013). Deciphering mutant ELOVL4 activity in autosomal dominant Stargardt Macular Dystrophy. Proc. Natl. Acad. Sci. USA, 110:5446-51. Mar 18. [Epub ahead of print]. PMC3619277
12. Rajala A, Gupta, VK, Anderson RE, Rajala RVS. (2013). Insulin-phosphoinositide 3-kinase pathway regulates hexokinase-mitochondria
Dean A. McGee Eye Institute
Department of Ophthalmology
608 Stanton L. Young, Blvd.
Oklahoma City, OK 73126-0901
Phone: (405) 271-8250
Fax: (405) 271-8120 Robert-Anderson@ouhsc.edu