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

Publisher: Association For Research In Vision And Ophthalmology (Arvo) Country of Publication: United States NLM ID: 7703701 Publication Model: Print Cited Medium: Internet ISSN: 1552-5783 (Electronic) Linking ISSN: 01460404 NLM ISO Abbreviation: Invest Ophthalmol Vis Sci Subsets: MEDLINE

Publication: Brookline Ma : Association For Research In Vision And Ophthalmology (Arvo)
Original Publication: St. Louis, Mosby.

Disease Models, Animal* ; Sphingolipids*/metabolism ; Retinal Pigment Epithelium*/metabolism ; Retinal Pigment Epithelium*/pathology ; Mice, Knockout* ; Sphingomyelin Phosphodiesterase*/metabolism ; Sphingomyelin Phosphodiesterase*/genetics; Animals ; Mice ; Retinal Degeneration/metabolism ; Vitamin A/metabolism ; Mice, Inbred C57BL ; Retinal Rod Photoreceptor Cells/metabolism ; NADP/metabolism ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Retina/metabolism ; Chromatography, Liquid

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.

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R01 EY014850 United States EY NEI NIH HHS

0 (Sphingolipids)
EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
11103-57-4 (Vitamin A)
53-59-8 (NADP)

Date Created: 20241211 Date Completed: 20241211 Latest Revision: 20241215

20241215

PMC11640910

10.1167/iovs.65.14.24

39661357