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William C Gordon, Nicolas G Bazan; Lack of n3 VLC-PUFAs and Elovanoids correlates with impaired photoreceptor disk morphogenesis in AdipoR1 KO. Invest. Ophthalmol. Vis. Sci. 2018;59(9):986.
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© ARVO (1962-2015); The Authors (2016-present)
Docosahexaenoic acid (DHA) plays a key role in vision, neuroprotection, successful aging, and memory, and modulates inflammatory responses. The n3 Very Long Chain-PolyUnsaturated Fatty Acids (VLC-PUFA) are precursors of a new family of lipid mediators, the elovanoids (ELV), and under stress DHA and 32- and/or 34-carbon VLC-PUFAs are cleaved from phosphatidylcholine (PC) and transformed into NeuroprotectanD1 (NPD1) and ELVs. In AdipoR1 KO mice, DHA uptake by photoreceptors (PR) and RPE is blocked so key VLC-PUFAs are lacking; NPD1 and ELV synthesis cannot occur. This EM study describes the retinal degeneration which results from lack of NPD1 and ELV protection.
WT and AdipoR1 KO mice were processed for TEM by conventional methods.
AdipoR1 KO mice have greatly reduced retinal DHA, and we have found abnormal disk morphogenesis highlighted by disorganization and PR degeneration, accompanied by subretinal macrophage/microglial accumulation. Disk synthesis begins at PN 8-9 days with expanded, balloon-like figures which gradually compress into flattened, elongated disks, to form crozier-like outer segments (OS) and vertically-oriented packets. OSs do not acquire normal lengths, becoming disoriented and degraded. Phagocytic accessory cells appear by PN 30, accumulating as dense subretinal arrays. By 10 months one row of cone nuclei remain; these cells have reduced inner segments (IS) which contain mitochondria, but which are devoid of OSs.
DHA and VLC-PUFAs are necessary components for PR maturation and disk morphogenesis. Molecules necessary for limiting disk growth, disk edge folding, and closure (eg, ROM1 and peripherin/rds) require membrane fluidity, provided by VLC-PUFA–containing molecular species of PC. Greatly reduced DHA (therefore, lack of n3 VLC-PUFAs and their ELVs) prevents homeostatic regulation for OS organization, and facilitates macrophage/microglia influx. Cone DHA uptake is much less than in rods; however, final loss of cone OSs suggests a cone DHA requirement as well. While inflammatory events trigger DHA and VLC-PUFA release from PCs and conversion to NPD1 and ELVs for homeostatic neuroprotection and restoration, loss of these signaling molecules allows uncompensated stress which, in turn, sets in motion further homeostatic disturbances, activation of apoptotic pathways, and PR cell death.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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