Novel role of very long chain fatty acids in the brain

University Of Oklahoma Hlth Sciences Ctr, Oklahoma City OK

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Abstract

DESCRIPTION (provided by applicant): Our lab was the first to discover that ELOngation of Very Long chain fatty acids-4 (ELOVL4) is an elongase responsible for biosynthesis of very long chain (VLC; eC26) fatty acids that are found as components of more complex lipid molecules such as sphingolipids and phosphatidylcholine. ELOVL4 synthesizes the VLC polyunsaturated fatty acids (VLC-PUFA) found in retina and testes, and VLC saturated fatty acids (VLC-FA) in skin and brain. Heterozygous inheritance of mutant ELOVL4, which lacks the ability to synthesize these fatty acids, causes juvenile macular degeneration in autosomal dominant Stargardt's macular dystrophy (STGD3). Humans with homozygous inheritance of the STGD3 mutation (ELOVL4 mutant/mutant), and thus make no VLC- PUFA/VLC-FA, develop ichthyosis, seizures, intellectual disability, and spastic quadriplegia, and die within the first few years of ife. This establishes a causal link between the mutation in ELOVL4 to a neurodegenerative disease; other than that, nothing is known about the role and importance of VLC-FA in the brain. Our group showed that VLC-FA are in sphingolipids in the rat brain. We have successfully generated an animal model that recapitulates the human condition. This unique animal model will enable us to study the role of ELOVL4 and VLC-FA in neural cell development, structure and function, which is a novel and unexplored area of research. Our central hypothesis is that VLC-FA play an important role in the development/maintenance of as yet undescribed activities in the CNS and that mutations in ELOVL4 and/or loss of VLC-FA lead to impaired neural function, evident by hyper-excitability and seizures. This novel hypothesis and the studies proposed herein to test it will allow us to break new ground in understanding neural development and the biological role of ELOVL4 and its VLC-FA products in the brain. We propose the following three specific aims to test our hypothesis. In this R21 application, we propose a series of experiments that will provide us with the basic information we will need to submit an R01 application in the second year. 1. To test the hypothesis that a loss of VLC-FA within the CNS is sufficient to cause impaired neural development leading to neural dysfunction and seizures. 2. To characterize the expression pattern of ELOVL4 and its products within the CNS. 3. To determine the mechanism of neural dysfunction mediated by mutations in ELOVL4 and/or loss of VLC-FA.