Defining the Mechanism of Altered Very Long Chain Fatty Acid Metabolism in Neuro-Ichthyotic Disorders.

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Mutations in the Elongation of Very Long Chain Fatty Acids-4 (ELOVL4) gene cause neuro-ichthyotic disorder characterized by dry scaly skin (ichthyosis) and cognitive deficits, seizures and age-related cerebellar degeneration. ELOVL4 is an essential enzyme that mediates biosynthesis of very long chain (≥C28) saturated (VLC-SFA) and polyunsaturated fatty acids (VLC-PUFA) that are collectively called very long chain fatty acids (VLC-FA). ELOVL4 is expressed in specific tissues in which it exhibits tissue-specific selectivity towards VLC- SFA and/or VLC-PUFA biosynthesis. In the skin, brain and Meibomian glands, ELOVL4 makes mainly VLC- SFA, while in the retina and testes it makes VLC-PUFA. However, the mechanisms by which one tissue makes VLC-SFA and the other VLC-PUFA, and how these VLC-FA exert their important protective roles in each tissue, remain unknown. Considering the fact that mutations in ELOVL4 affect skin and neuronal tissues, the answer must be in either the innate enzyme activity of the different mutant proteins or in a dominant negative effect of the mutant proteins on the quality and quantity of VLC-FA synthesized by the WT enzyme. The objective of this proposal is to examine what factors determine the tissue-specific selectivity of VLC-SFA biosynthesis relative to VLC-PUFA and how mutant ELOVL4 alters such factors to cause the different tissue- specific disorders. To achieve his goal, we generated the first Long Evans rat model of ELOVL4 mutation (c.736T>G, p.W246G) that causes Spinocerebellar ataxia 34 (SCA34) with Erythrokeratodermia variabilis (EKV). Compared to wild type control rats, heterozygous and homozygous SCA34 rats developed skin lesions from birth and later showed signs of cerebellar dysfunction typical of the human disease19. Analysis of skin VLC-SFA showed that the homozygous KI tissue had only about 33% of total VLC-SFA compared to WT controls. These findings indicate that the neuro-ichthyotic pathology in this mutant SCA34 model is likely caused by decreased skin and neuronal VLC-FA levels, an effect of the ELOVL4 mutation. We hypothesize that tissue-specific factors determine which type of VLC-FA (saturated versus polyunsaturated) is made and that the skin and cerebellar pathological defects found in SCA34 patients result from effects of the mutant ELOVL4 enzyme on the wild type ELOVL4’s ability to synthesize VLC-FA. We propose two specific aims to test this hypothesis. Upon successful completion of the proposed experiments, we will answer unresolved questions of how the different mutant ELOVL4 proteins affect VLC-FA biosynthesis to cause neuro-ichthyotic disorders. We anticipate this will allow us to pursue experimental treatment options in future studies which could progress rapidly into human clinical trials for treating some of the human mutant ELOVL4 disorders.