What Triggers Mutant ELOVL4 Induced Blindness in STGD3?
Detailed Non-Technical Summary
Dr. Agbaga has a long-term research interest to combine advances in molecular biology, lipidomics, proteomics, and biochemical assays to dissect the mechanism underlying blinding eye diseases. In particular, his goal is to discover, develop, and evaluate possible future treatments for macular degenerative diseases such as STGD3 and AMD, both of which have no known cures. Currently Dr. Agbaga’s team is working on understanding what causes macular degeneration in teenagers with inherited mutations in a gene called Elongation of Very Long Chain Fatty Acids-4 (ELOVL4). Inheritance of a single copy of the mutant ELOVL4 gene is sufficient to induce blindness in STGD3 patients by their teenage years. The team was the first to show that the normal ELOVL4 protein makes the unique combination of omega-3 and omega-6 fatty acids that are found in the retina. Presence of the mutant ELOVL4 decreases the amount of these fatty acids in the retina. At the same time, the mutant ELOLV4 protein seems to have a negative influence on the normal ELOVL4 protein, causing it to be misrouted to the wrong cellular compartments in photoreceptor cells. Thus, it is not clear whether the mutant ELOVL4 induces macular degeneration through dominant negative (loss-of-function) or toxic gain-of-function mechanisms – either is possible.
With the grant from the BrightFocus Foundation, the team will focus on identification of proteins that interact in vivo with the mutant ELOVL4 to exert a dominant negative effect on the normal ELOVL4, and how misrouting of the mutant ELOVL4 to photoreceptor outer segments (the part of the cell that absorbs light) leads to early onset retinal cell death in STGD3 patients. The team will achieve these goals by using novel molecular and biochemical approaches that they and others have developed. Successful completion of the experiments will help to better understand the mechanisms that induce macular degeneration in STGD3. They hope to develop experimental therapeutic approaches to inhibit the dominant negative influence of the mutant ELOVL4 protein on the normal ELOVL4 protein by using chemical and molecular inhibitors on animal models of the human disease. If they successfully rescue photoreceptor degeneration in these STGD3 models with their novel approach, they could progress into human clinical trials for treating STGD3 patients. Since macular dystrophy in STGD3 shares similar pathological features with dry AMD, understanding the mechanism that signals cell death in STGD3 animal models will help with the design of effective therapeutic strategies for both STGD3 and some forms of dry AMD.