Very Long Chain Polyunsaturated Fatty Acids and Rod Cell Structure and Function

Abstract

The gene encoding Elongation of Very Long Chain Fatty Acids-4 (ELOVL4) is mutated in patients with autosomal dominant Stargardt's Macular Dystrophy Type 3 (STDG3). ELOVL4 catalyzes the initial condensation step in the elongation of polyunsaturated fatty acids (PUFA) containing more than 26 carbons (26C) to very long chain PUFA (VLC-PUFA; C28 and greater). To investigate the role of VLC-PUFA in rod photoreceptors, we generated mice with rod-specific deletion of Elovl4 (RcKO). The mosaic deletion of rod-expressed ELOVL4 protein resulted in a 36 % lower amount of VLC-PUFA in the retinal phosphatidylcholine (PC) fraction compared to retinas from wild-type mice. However, this reduction was not sufficient to cause rod dysfunction at 7 months or photoreceptor degeneration at 9 or 15 months.

Mouse Models of Stargardt 3 Dominant Macular Degeneration

“…Other STGD3 mouse models include transgenic mice that express either human wild type or mutant ELOVL4 (Karan et al 2005; Kuny et al 2010, 2012; Barabas et al 2013) or cell specific knockdowns where mouse Elovl4 was knocked out specifically from cones (Harkewicz et al 2012; Barabas et al 2013) or rods (Harkewicz et al 2012; Barabas et al 2013; Marchette et al 2014) or the entire retina (Bennett et al 2014a, 2014b). Unexpectedly, only the transgenic strains show early onset photoreceptor degeneration (Karan et al 2005; Kuny et al 2010, 2012) with onset time and severity depending on transgene expression level.…”

Current Progress in Deciphering Importance of VLC-PUFA in the Retina

“…This is obviated when the reduction of retinal VLC-PUFAs are considered (Table 20.1). These fatty acids were decreased by 36-97 % of WT values in the R-cKO and RC-cKO mice (Harkewicz et al 2012;Barabas et al 2013;Bennett et al 2014b;Marchette et al 2014). The VLC-PUFA levels in the cone-specific Elovl4 ablated mice (C-cKO) were unaffected (Table 20.1), but this could be due to the fact that mice are rod-dominant and that these fatty acids comprise only 12 % of the total fatty acids in the retina (Rotstein and Aveldano 1988).…”

“…Harkewicz et al (2012) reported that rod-specific Elovl4 conditional KO (R-cKO) mice had retinal degeneration at 10 and 15 months of age, whereas Barabas et al (2013) and Marchette et al (2014) did not find photoreceptor degeneration in R-cKO mice at 7 and 15 months, respectively. Harkewicz et al (2012) found R-cKO mice had decreased rod b-wave responses, but Barabas et al (2013) and Marchette et al (2014) did not find rod-mediated deficits in their 6-or 7-monthold R-cKO mice, respectively. When Elovl4 was deleted from both rods and cones (RC-cKO), retinal degeneration occurred and rod ERG responses were decreased in 12-month-old mice (Bennett et al 2014b).…”

“…Removal of Elovl4 expression in rods, cones, or both rods and cones has been achieved by breeding mice expressing Cre-recombinase driven by different photoreceptor specific promoters to Elovl4 flox/flox mice (Harkewicz et al 2012;Barabas et al 2013;Bennett et al 2014b;Marchette et al 2014). Cone-specific human redgreen pigment (HRGP)-Cre-and rod-specific Opsin-cre-or opsin-iCre75-expressing mice were used to delete Elovl4 from cones and rods, respectively, whereas Elovl4 was deleted from both photoreceptor types using Chx10-cre-expressing mice (Harkewicz et al 2012;Barabas et al 2013;Bennett et al 2014b).…”

“…Harkewicz et al (2012) used generic WT mice whereas Barabas et al (2013), Bennett et al (2014b), and Marchette et al (2014) used Cre…”