Abstract
Purpose :
Progranulin (PGRN), a glycoprotein secreted by macrophages and microglial cells, plays a pivotal role in regulating cell growth, survival, repair, inflammation, and lysosomal function. Mutations in the Progranulin gene (GRN) can result in frontotemporal degeneration (FTD) and neuronal ceroid lipofuscinosis (NCL), both of which are associated with retinal degeneration and visual dysfunction. This study aims to identify the ocular phenotype and potential visual dysfunction in GRN knockout mice, with the ultimate goal of establishing these mice as a model for GRN mutation associated eye disorders.
Methods :
We used 2, 7, 12, and 14-month-old GRN mice (WT, n=41; KO, n=44, Regeneron Pharmaceuticals Inc) for the study. Fundus images were taken over time to monitor retinal changes, including autofluorescence. Optical Coherence Tomography (OCT, Heidelberg Engineering, Germany) was used for in vivo evaluation of the mouse retina. Retinal layer segmentation analysis and histological evaluation were conducted to compare the retinal thickness and morphology of age matched GRN WT and KO mice. Electroretinogram (ERG) was performed to assess the visual function.
Results :
OCT imaging and whole retina thickness analysis showed significant retinal thinning at 2 months age old GRN KO mice (WT 246.91±0.8µm; n=11. KO 232.46±1.84µm; n=11. p<0.0001) and follow up same group of animals at 14 months of age (WT 249.82±1.05µm; KO 229.64±2.52µm, p<0.0001). The ERG analysis showed a significant reduction of scotopic a-wave amplitude in GRN KO mice at 2 months of age, with further declines at 14 months comparing with their age matched WT mice.
Conclusions :
We shown retinal degeneration and rod photoreceptor function loss in GRN knockout mice. These results suggest that progranulin plays a crucial role in ocular tissues, particularly in maintaining the structure and function of photoreceptors. Therefore, the GRN knockout mouse serves as a valuable model to provide insights into the therapeutic strategies for GRN mutation associate eye disorders.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.