Abstract
Elongation of Very Long chain fatty acids-like 4 (ELOVL4) is a fatty acid elongase responsible for the biosynthesis of very long chain (VLC; ≥ C26) fatty acids in the retina, brain, skin, Meibomian gland, and testes. Heterozygous inheritance of mutant ELOVL4 causes juvenile macular degeneration in autosomal dominant Stargardt-like macular dystrophy (STGD3). Retinal photoreceptors are enriched with VLC polyunsaturated fatty acids (VLC-PUFAs), which have been shown by our group and others to be necessary for the survival of rod photoreceptors. Our group performed a series of studies using mice conditionally depleted of retinal Elovl4 (KO) aimed at understanding the role of VLC-PUFAs in long-term retinal health and function, focusing on the role of these fatty acids in mediating synaptic function between the photoreceptors and the rest of the neural retina. The absence of VLC-PUFA from the retina of KO mice resulted in a marked decrease in retinal b-wave responses of the electroretinogram as well as a decrease in the amplitude of the oscillatory potentials mediated by the neural retina. Although there were no measureable differences between KO and wild type (WT) mice in either pre-synaptic rod calcium channel function or post-synaptic bipolar cell glutamate receptor responses, ultrastructural analysis revealed a marked decrease in the diameter of synaptic vesicles in rod terminals. Recent quantification suggests that this decrease in synaptic vesicle size due to the absence of VLC-PUFAs in KO mice, and the consequent decrease in glutamate content, could account for the decrease in b-wave response amplitudes that were previously measured in these animals.
Highlights
Elongation of Very Long chain fatty acids-like 4 (ELOVL4) is a fatty acid elongase responsible for the biosynthesis of very long chain (VLC; ≥ C26) fatty acids that are found as components of more complex lipid molecules such as sphingolipids and phospholipids in the retina, brain, skin, Meibomian gland, and testes (Agbaga et al, 2008; Aveldano, 1987; Brush et al, 2010; Poulos et al, 1987; Vasireddy et al, 2007)
Our studies demonstrate a clear role for ELOVL4 in supporting the structural and functional integrity of neuronal synapses within the mammalian retina
VLC-PUFA are not exclusively expressed in photoreceptor outer segments as was previously thought, but rather are present within both the large ribbon synapses made up of the photoreceptor and bipolar cells as well as the smaller conventional synapses utilized by the rest of the neural retina
Summary
Elongation of Very Long chain fatty acids-like 4 (ELOVL4) is a fatty acid elongase responsible for the biosynthesis of very long chain (VLC; ≥ C26) fatty acids that are found as components of more complex lipid molecules such as sphingolipids and phospholipids in the retina, brain, skin, Meibomian gland, and testes (Agbaga et al, 2008; Aveldano, 1987; Brush et al, 2010; Poulos et al, 1987; Vasireddy et al, 2007). Using in vitro cell-based and cell-free microsomal assays, we found that coexpression of different forms of both wild-type and mutant ELOVL4 resulted in a significant dominant-negative effect of the mutant protein on both localization and enzymatic activity of the wild-type protein (Logan et al, 2013). This suggests that the retina phenotype observed in STGD3 results from a loss of VLC-PUFA products due to the dominant negative effect of an enzymatically inactive mutant protein. Function, synaptic architecture, and the ultrastructure of VLCPUFA-depleted photoreceptor terminals (Bennett et al, 2014)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
