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E. F. Nandrot, N. Brot, S. C. Finnemann; Impact of Lack of Methionine Sulfoxide Reductase a (MsrA) on Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5184.
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Retinal cells are exposed to constant high levels of oxidative stress. Oxidative damage is associated with retinal diseases including age-related macular degeneration. Detoxifying enzymes of retinal cells are thus likely of crucial importance for long-term retinal health and vision. Methionine sulfoxide reductase A (MsrA) enzymatically reverses oxidation of protein methionine residues that are primary targets of reactive oxygen species. In monkey retina, MsrA protein mainly localizes to the retinal pigment epithelium (RPE), photoreceptor synapses and ganglion cells. Here, we studied how constitutive lack of MsrA affects RPE and neural retina phenotype and function of MsrA knockout (MsrA-/-) mice.
We tested retinal function by recording scotopic electroretinograms (ERGs) of MsrA-/- mice at 4 and 16 months of age. We studied diurnal photoreceptor outer segment phagocytosis by MsrA-/- RPE in the retina by quantifying the phagosome load of the RPE with time of day. We compared wild-type and MsrA-/- retinal morphology, RPE autofluorescence and expression of marker proteins for specific retinal cell types by light and fluorescence microscopy of labeled eye paraffin and cryosections. We quantified expression of the same retinal markers by comparative immunoblotting.
MsrA-/- retinal morphology appeared grossly normal at all ages. We found similar expression patterns of most retinal markers in MsrA-/- and wild-type mice. MsrA-/- RPE showed normal peak phagosome numbers following light onset. However, MsrA-/- RPE accumulated excess levels of autofluorescent lipofuscin-like cytoplasmic granules with age. Strikingly, amplitudes of ERG b-waves but not a-waves were significantly smaller in MsrA-/- than in control mice at both ages tested.
Our results imply that lack of the anti-oxidant enzyme MsrA may impact more than one retinal cell type: (1) Accumulation of lipid deposits in MsrA-/- RPE cells suggests that these cells may accumulate defects with age that delay phagolysosomal digestion. However, such RPE damage does not significantly impair RPE functions in support of photoreceptor cells, since ERG a-waves indicative of photoreceptor function remain normal. (2) Decreased b-wave amplitudes in young and old MsrA-/- mice suggest constitutive defects in neural transmission of light signals beyond phototransduction. Studies are underway to fully elucidate these defects linked to absence of MsrA protein in the mouse retina.
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