Martin-Paul Agbaga, Ph.D

Oklahoma University Health Science Center - New Investigator

Project Title: Understanding the role of ELOVL4 protein and very long chain polyunsaturated fatty acids in retinal degeneration

 

Juvenile autosomal dominant Stargardt-like macular dystrophy (STGD3) is an inherited blinding disease in humans in which retina cells which allow for day time and fine vision are progressively destroyed. Since the retinal cells are non-replaceable once they die, patients progressively lose their central vision and eventually become blind. Three different forms of dominantly inherited mutations in a gene named ELOngation of Very Long chain fatty acids-4 (ELOVL4) has been associated with the disease. In other words, inheriting one bad copy of the gene from either parent is enough to cause the disease. From our studies and that of others, we have reasoned that there are two major possibilities that may be contributing to the death of the retinal cells in patients. In the first scenario, we know that the mutant protein loses its ability to be delivered to its proper place in cells and so it gets mislocalized. As a result, we think that, by being constantly delivered to and accumulating at the wrong “address” and generating toxic intermediate products that cannot be effectively cleared by the cells, the mutant protein
might be exerting cellular stress on the retinal cells. These eventually cause the retinal cells to die with a resultant loss of vision. We therefore seek to understand what role(s) the mutant protein plays in causing retinal cell death.

In the second scenario, we know that animals expressing one normal copy and one “bad” copy of
the ELOVL4 protein have reduced levels of a unique group very long chain polyunsaturated fatty acids (VLC-PUFA), of the omega-3 and -6 families of fatty acids. These fatty acids are found in tissues which express ELOVL4: the retina, testis, sperm, and brain. We have shown that the wild type ELOVL4 protein is involved in biosynthesis of VLC-PUFA. We believe that VLC-PUFA together with other omega 3 and 6 fatty acids play very important roles in the retina, hence their loss/reduction in the disease situation causing the cells to die. We reason that this loss/reduction in VLC-PUFA due to the misrouting of both mutant and the wild type protein from the site where these fatty acids are made and where the normal ELOVL4 protein are normally delivered, causes the photoreceptor cells to die. This suggests that, if indeed loss of VLC-PUFA is the cause of retinal degeneration in STGD3 patients, then dietary feeding or other innovative ways to specifically deliver VLC-PUFA to the retina of patients will provide some therapeutic benefits and prevent or delay death of the retina cells.

By finding answers to the two scenarios discussed above, we believe that we will have a better
understanding of the details of WHY and HOW the retina cells are destroyed so that we will be able to better define and design effective therapeutic strategies to prevent or at least delay the onset of retinal cell death in STGD3 patients.