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V. Vasireddy, M. M. Jablonski, X. Wang, P. Sahu, J. Sparrow, R. Ayyagari; Accumulation of ELOVL4 and Elevation of RPE Lipofuscin Pigments in Elovl4 5-bp Deletion Knock in Mice. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3057.
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To investigate the pathogenic mechanism associated with Stargardt like macular degeneration (STGD3) due to a 5-bp deletion mutant ELOVL4 and disease progression at older age, e studied the retinal pathology in the heterozygous ELOVL4 5-bp deletion knock-in (E_mut+/-) mouse model
Photoreceptor degeneration in older E_mut+/- mice aging 20-24 months was studied by evaluating morphology. Localization of ELOVL4 in retinal tissue was determined by immuno electron microscopy and immunofluorescence. Accumulation of ELOVL4 was determined by Western blot analysis. Levels of the RPE lipofuscin pigments A2E, iso-A2E all-trans-retinal dimer-phosphatidylethanolamine (atRAL dimer-PE) and all-trans-retinal dimer-ethanolamine (atRAL dimer-E) were measured by quantitative HPLC with normalization to external standard at various ages. Mice were genotyped for RPE65 Leu450Met. Number of lipofuscin granules in the RPE of E_mut+/-mice was also determined and compared with the controls.
Accumulation of ELOVL4 was observed in the inner segments and outer plexiform layer (OPL) of the retina in E_mut+/- mice compared to controls. Immunoelectron microsopic evaluation of retinal sections of E_mut+/- mice also supported the localization and accumulation of ELOVL4 in OPL. Immunofluorescence and Western blot analysis further confirmed the accumulation of ELOVL4 in E_mut+/- mice. The levels of A2E and iso-A2E did not show a significant variation between E_mut+/- and control mice retina at 2 month. However at 4 and 10 months of age there was a significant elevation (P= 0.04 & 0.02, respectively) of A2E and iso-A2E content in E_mut+/- mice compared to controls. The number of lipofuscin granules in retinal sections were also found to be significantly higher in E_mut+/- mice in comparison to the controls.
The accumulation of ELOVL4 in the retina and the elevated levels of nondegradable fluorophores in RPE of E_mut+/- mice may contribute to photoreceptor degeneration in E_mut+/- mice.
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