Abstract
Purpose: :
The prevalence of age-related retinal degenerative disorders is rising as the North American population becomes increasingly aged. The genetic basis of human aging has a mouse model in the harlequin (hq) mouse which features an early retinal degenerative phenotype. The hq disease mutant features vision deficits at 2 months and structural losses at 4 months and is characterized by an 80% downregulation of the Apoptosis-inducing factor (Aif) gene. Early-onset retinal degeneration is hypothesized as a result of parainflammatory pathway activation resulting in upregulation of the Major Histocompatibility Complex I (MHC-I) genes (H2-K1, B2M).
Methods: :
The Taqman® real-time polymerase chain reaction assay was used to quantify changes in gene expression of n=3 wild type and n=3 hq disease mice at 7 weeks, 4 months and 7 months of age. In vivo imaging was performed with the Heidelberg Spectralis® Spectral Domain Optical Coherence Tomography (OCT) on n=3 wild type and n=3 hq disease mice at 7 weeks, 4 months and 7 months of age. Retinal layer thickness was measured with the Heidelberg Eye Explorer® software.
Results: :
At 7 months of age, MHC I genes H2-K1 and B2M show a 10-fold and 5-fold significant increase in gene expression in the hq disease mouse compared to wild type (p < 0.001). H2-K1 is significantly upregulated 2-fold at both 7 weeks and 4 months compared to wild type (p < 0.05). B2M is significantly upregulated 2-fold at 4 months of age compared to wild type (p < 0.05). At 7 months of age, in vivo imaging of the hq disease mouse shows the outer nuclear layer and retina are significantly thinner than the wild type (p < 0.05).
Conclusions: :
Changes in gene expression indicate that the immune response is highly active in the hq disease mouse between 4 months and 7 months of age. The increase of MHC-I gene expression is significantly upregulated when compared to the wild type mouse. In vivo imaging with Spectralis® identified the earliest evidence of significant retinal thinning assessed in vivo of the hq mouse. Cellular response to immune system activation will be confirmed by in situ tracking of microglial migration. Thinning of the retina is seen in normal human aging, and these results establish a time frame correlated to changes in immune response gene expression. This time frame is ideal to test potential drug targets to prevent or treat retinal degeneration.
Keywords: gene/expression • retinal degenerations: cell biology • microglia