Sphingolipid Levels and Processing of the Retinyl Chromophore in the Retina of a Mouse Model of Niemann-Pick Disease.

Purpose: Mutations in the gene that encodes the enzyme acid sphingomyelinase (ASMase) are associated with Niemann-Pick disease, a lysosomal storage disorder. Mice that lack ASMase (ASMase-/-) exhibit age-related retinal degeneration and large increases in accumulation of lipofuscin in the retinal pigment epithelium (RPE). We examined which lipid species accumulate in the retina and the RPE of ASMase-/- mice and whether the retinal degeneration is associated with impaired photoreceptor metabolism and retinyl chromophore processing.

Methods: NADPH availability and all-trans retinol formation after rhodopsin bleaching were measured in isolated single rod photoreceptors with fluorescence imaging; sphingolipid levels in retinas and RPEs were measured with LC/MS; relative abundances of different lipid species in different retinal layers were measured with MALDI imaging mass spectrometry.

Results: There was no detectable difference in the kinetics of all-trans retinol formation or the NADPH-generating capacity between ASMase-/- and wild-type mice. Sphingomyelin levels were much higher in the retinas and RPEs of ASMase-/- animals compared to wild type, but there were no significant differences for ceramides. There was a large increase in the abundance of bis(monoacylglycero)phosphates (BMPs) in ASMase-/- mice, indicative of lysosomal dysfunction, but no substantial changes were detected for the bis-retinoid A2E.

Conclusions: Lysosomal dysfunction and retinal degeneration in ASMase-/- mice are not associated with defects in rod photoreceptor metabolism that affect all-trans retinol formation and availability of NADPH. Lysosomal dysfunction in ASMase-/- mice is not associated with bis-retinoid A2E accumulation.