Abstract
Purpose :
Progranulin (PGRN) is a widely expressed glycoprotein that has been studied in the context of neurodegeneration. PGRN deficiencies have been linked to conditions such as frontotemporal dementia (FTLD) and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. PGRN has been implicated in phagocytosis, a process crucial for retinal homeostasis and the daily visual cycle. The TAM receptors (Tyro3, Axl, and Mer) are tyrosine kinases that are instrumental to the phagocytic process. We hypothesize that Axl is an inflammatory mediator of phagocytosis in murine eyes with PGRN deficiencies.
Methods :
Enucleated eyes from 3- and 18-month-old wild-type (WT) and PGRN-knockout (KO) mice were cut and mounted onto silinized slides. Samples were processed and stained with primary antibodies against Axl, fluorescence-conjugated secondary antibodies, and nuclear Hoescht stain before being subsequently visualized via microscopy. Immunofluorescence and tissue thickness measurements were quantified via ImageJ. ANOVA and unpaired t-test were used for statistical analysis.
Results :
In this study, we demonstrate that retinas from 18-month-old PGRN KO mice (n=7) exhibit increased Axl expression compared to age-matched controls (n=6, p<0.05), while there is no difference between 3-month-old PGRN KO (n=5) and age-matched controls (n=3, p>0.05). Furthermore, Axl expression is specifically upregulated in the ganglion cell layer, the innermost retinal layer composed of neurons that relay information from the visual field to the visual cortex, forming the optic nerve.
Conclusions :
These results suggest that as these KO mice age, there is an inflammatory process involved in the degeneration of their retinas, specifically highlighting Axl as a mediator of the degenerative phenotype. This could potentially implicate Axl as a player in the visual loss experienced by patients with PGRN deficiencies, such as those with FTLD or NCL. Future work will examine whether blocking Axl is protective in PGRN-mediated retinal degeneration.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.