Role of ELOVL4 and very long-chain polyunsaturated fatty acids in mouse models of Stargardt type 3 retinal degeneration

Abstract

Stargardt type 3 (STGD3) disease is a juvenile macular dystrophy caused by mutations in the ELOVL4 (Elongation of very long chain fatty acids 4) gene. Its protein product, ELOVL4, is an elongase required for the biosynthesis of very long-chain polyunsaturated fatty acids (VLC-PUFAs). It is unclear whether photoreceptor degeneration in STGD3 is caused by loss of VLC-PUFAs or by mutated ELOVL4 protein trafficking/aggregation. We therefore generated conditional knockout (cKO) mice with Elovl4 ablated in rods or cones and compared their phenotypes to transgenic (TG) animals that express the human STGD3-causing ELOVL4 STGD3 allele. Gas chromatography-mass spectrometry was used to assess C 30 -C 34 VLC-PUFA and N-retinylidene-N-retinylethanolamine content; electroretinography was used to measure phototransduction and outer retinal function; electron microscopy was used for retinal ultrastructure; and the optomotor tracking response was used to test scotopic and photopic visual performance. Elovl4 transcription and biosynthesis of C 30 -C 34 VLC-PUFAs in rod cKO and TG retinas were reduced up to 98%, whereas the content of docosahexaenoic acid was diminished in TG, but not rod cKO, retinas. Despite the near-total loss of the retinal VLC-PUFA content, rod and cone cKO animals exhibited no electrophysiological or behavioral deficits, whereas the typical rod-cone dystrophic pattern was observed in TG animals. Our data suggest that photoreceptor-specific VLC-PUFA depletion is not sufficient to induce the STGD3 phenotype, because depletion alone had little effect on photoreceptor survival, phototransduction, synaptic transmission, and visual behavior.

Long-Term Retinal Cone Survival and Delayed Alteration of the Cone Mosaic in a Transgenic Mouse Model of Stargardt-Like Dystrophy (STGD3)

“…Hence, it is very likely that the early rod loss seen in TG at 2 months 39 involves mechanisms other than decreased levels of VLC-PUFA. This is in agreement with the findings of Barabas et al,9 in which close to complete depletion of very long chain fatty acids in conditional ELOVL4 knockouts did not result in photoreceptor cell loss. The drastic decline of the total n-3 C32 and C34 VLC-PUFA in TG was seen beyond 12 months.…”

Long-Term Retinal Cone Survival and Delayed Alteration of the Cone Mosaic in a Transgenic Mouse Model of Stargardt-Like Dystrophy (STGD3)

“…Hence, it is very likely that the early rod loss seen in TG at 2 months 39 involves mechanisms other than decreased levels of VLC-PUFA. This is in agreement with the findings of Barabas et al,9 in which close to complete depletion of very long chain fatty acids in conditional ELOVL4 knockouts did not result in photoreceptor cell loss. The drastic decline of the total n-3 C32 and C34 VLC-PUFA in TG was seen beyond 12 months.…”

Retinal Degenerative Diseases

“…Despite the minimal decrease in VLC-PUFAs, found that Elovl4 C-cKO mice had decreased cone flicker responses at 7 months of age compared to WT mice. These results are contrary to Barabas et al (2013) and Bennett et al (2014b), who did not find cone dysfunction at 6 and 12 months, respectively.…”

Retinal bioavailability and functional effects of a synthetic very-long-chain polyunsaturated fatty acid in mice

“…S4), suggestive of a mild photoreceptor degeneration. Our findings are consistent with previous reports of other Elovl4 knock-in and rod and/or cone conditional knockout mice that also showed ERG abnormalities and mild structural degeneration of the retina (32,34,35).…”

Long-Term Retinal Cone Survival and Delayed Alteration of the Cone Mosaic in a Transgenic Mouse Model of Stargardt-Like Dystrophy (STGD3)

“…Hence, it is very likely that the early rod loss seen in TG at 2 months 39 involves mechanisms other than decreased levels of VLC-PUFA. This is in agreement with the findings of Barabas et al,9 in which close to complete depletion of very long chain fatty acids in conditional ELOVL4 knockouts did not result in photoreceptor cell loss. The drastic decline of the total n-3 C32 and C34 VLC-PUFA in TG was seen beyond 12 months.…”

Retinal Degenerative Diseases

“…Despite the minimal decrease in VLC-PUFAs, found that Elovl4 C-cKO mice had decreased cone flicker responses at 7 months of age compared to WT mice. These results are contrary to Barabas et al (2013) and Bennett et al (2014b), who did not find cone dysfunction at 6 and 12 months, respectively.…”

Retinal bioavailability and functional effects of a synthetic very-long-chain polyunsaturated fatty acid in mice

“…S4), suggestive of a mild photoreceptor degeneration. Our findings are consistent with previous reports of other Elovl4 knock-in and rod and/or cone conditional knockout mice that also showed ERG abnormalities and mild structural degeneration of the retina (32,34,35).…”

Long-Term Retinal Cone Survival and Delayed Alteration of the Cone Mosaic in a Transgenic Mouse Model of Stargardt-Like Dystrophy (STGD3)

“…Hence, it is very likely that the early rod loss seen in TG at 2 months 39 involves mechanisms other than decreased levels of VLC-PUFA. This is in agreement with the findings of Barabas et al,9 in which close to complete depletion of very long chain fatty acids in conditional ELOVL4 knockouts did not result in photoreceptor cell loss. The drastic decline of the total n-3 C32 and C34 VLC-PUFA in TG was seen beyond 12 months.…”

Retinal Degenerative Diseases

“…Despite the minimal decrease in VLC-PUFAs, found that Elovl4 C-cKO mice had decreased cone flicker responses at 7 months of age compared to WT mice. These results are contrary to Barabas et al (2013) and Bennett et al (2014b), who did not find cone dysfunction at 6 and 12 months, respectively.…”

Retinal bioavailability and functional effects of a synthetic very-long-chain polyunsaturated fatty acid in mice

“…S4), suggestive of a mild photoreceptor degeneration. Our findings are consistent with previous reports of other Elovl4 knock-in and rod and/or cone conditional knockout mice that also showed ERG abnormalities and mild structural degeneration of the retina (32,34,35).…”