Abstract
Purpose: :
Mutations of acid sphingomyelinase (aSMase) cause Niemann-Pick diseases (NPD) type A and B, which are fatal inherited lipid lysosomal storage diseases, characterized with visceral organ abnormalities and neurodegeneration. However, the effect of the disruption aSMase on the retina is still unclear. The goal of this study is to determine if the disruption of aSMase will affect the visual functions in the mouse, and to further investigate mechanism underlying the neuronal abnormalities in the NPD type A disease.
Methods: :
ASMase knockout (KO) mice were used to study the roles of this sphingolipid metabolizing enzyme in the retina. The visual function of these animals was evaluated by electroretinogram (ERG) at various ages. Histological analysis, sphingolipid profile measurement, autophagy markers, and autofluorescence were examined in isolated retinae.
Results: :
Morphology analysis of aSMase KO retinas revealed degenerations in various retinal layers, especially the outer nuclear layer. Further, ERG responses were significantly decreased in KO mice in an age-dependent manner. Sphingolipid analyses showed abnormal accumulation of sphingomyelin and sphingosine in aSMase KO retinae. In addition, western blot analysis showed a higher level of an autophagosome marker, LC3-II, in aSMase KO retinae, suggesting that absence of aSMase results in retinal autophagy defects. In addition, lack of aSMase induced abnormal accumulation of GFAP and autofluorescence materials in retinae, which may contribute to stress signaling and neuronal degeneration in the aSMase KO retina.
Conclusions: :
Our study demonstrates that aSMase is necessary for the maintenance of the retinal structure and visual function and disruption of aSMase results in age-progressive retinal degeneration. Further, abnormal sphingolipid accumulation and autophagic activity may contribute to the retinal disorders in aSMase KO mice. The retinal phenotype in the aSMase KO mice suggests this animal may serve as a model for age-related degeneration of the retina.
Keywords: lipids • ipofuscin • age-related macular degeneration