title: Lack of Acid Sphingomyelinase Induces Age-Related Retinal Degeneration.
abstract: 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.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Bill X
authors.initials: BX
authors.lastname: Wu
authors.affiliation: Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Boyer
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Russell W
authors.initials: RW
authors.lastname: Jenkins
authors.affiliation: Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Yiannis
authors.initials: Y
authors.lastname: Koutalos
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America; Stony Brook Cancer Center and Department of Medicine, Stony Brook University, 100 Nicolls Rd., Stony Brook, New York, United States of America.
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.affiliation: Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Crosson
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D004596:Electroretinography; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055213:Retinal Pigment Epithelium / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism*
chemical_list: D013108:Sphingomyelin Phosphodiesterase