Journal
PLOS ONE
Volume 10, Issue 7, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0133032
Keywords
-
Categories
Funding
- National Institutes of Health (NIH) [EY021368, CA 097132]
- South Carolina Clinical & Translational Research (SCTR) institute with an academic home at the Medical University of South Carolina CTSA, NIH/NCATS [UL1TR000062]
- National Center for Research Resources
- Office of the Director of the National Institutes of Health [C06 RR018823]
- Research to Prevent Blindness (RPB) (New York, NY)
Ask authors/readers for more resources
Background Mutations of acid sphingomyelinase (ASMase) cause Niemann-Pick diseases type A and B, which are fatal inherited lipid lysosomal storage diseases, characterized with visceral organ abnormalities and neurodegeneration. However, the effects of suppressing retinal ASMase expression are not understood. The goal of this study was to determine if the disruption of ASMase expression impacts the retinal structure and function in the mouse, and begin to investigate the mechanisms underlying these abnormalities. Methods Acid sphingomyelinase knockout (ASMase KO) mice were utilized to study the roles of this sphingolipid metabolizing enzyme in the retina. Electroretinogram and morphometric analysis were used to assess the retinal function and structure at various ages. Sphingolipid profile was determined by liquid chromatography-mass spectrometry. Western blots evaluated the level of the autophagy marker LC3-II. Results When compared to control animals, ASMase KO mice exhibited significant age-dependent reduction in ERG a- and b-wave amplitudes. Associated with these functional deficits, morphometric analysis revealed progressive thinning of retinal layers; however, the most prominent degeneration was observed in the photoreceptor and outer nuclear layer. Additional analyses of ASMase KO mice revealed early reduction in ERG c-wave amplitudes and increased lipofuscin accumulation in the retinal pigment epithelium (RPE). Sphingolipid analyses showed abnormal accumulation of sphingomyelin and sphingosine in ASMase KO retinas. Western blot analyses showed a higher level of the autophagosome marker LC3- II. Conclusions These studies demonstrate that ASMase is necessary for the maintenance of normal retinal structure and function. The early outer retinal dysfunction, outer segment degeneration, accumulation of lipofuscin and autophagosome markers provide evidence that disruption of lysosomal function contributes to the age-dependent retinal degeneration exhibited by ASMase KO mice.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available