Abstract
Purpose :
Frontotemporal dementia (FTD) is the most common cause of cognitive deficits in people under the age of 65. Mutations in the GRN gene, which codes for progranulin, are implicated in FTD (GRN-FTD). Progranulin is a multifunctional protein that is thought to regulate lysosome function, inflammation, and neuronal health. Retinal deficits have been reported in GRN-FTD patients and Grn-/- mice. Despite these observations, precisely how the absence of progranulin results in retinal neurodegeneration remains unclear. Here, we identify novel mechanisms underlying retinal neurodegeneration in GRN-FTD and propose potential therapeutic approaches.
Methods :
Grn-/- mice were used to investigate the mechanisms by which progranulin loss causes retinal degeneration. Mouse RPE flatmounts, paraffin sections, RPE lysates were used for immunofluorescence imaging, retinal thickness measurements, and immunoblotting respectively. For a precise evaluation of mitochondrial dynamics, high-speed, high-resolution live imaging using spinning disc confocal microscopy was employed. RNA-seq analysis of RPE from 4 and 14-month-old mice was performed to identify novel pathways triggered by progranulin loss and validate our imaging data.
Results :
Paraffin sections and cryo-section staining showed a reduction in thickness of the outer nuclear layer (ONL) in 12- and 17-month-old Grn-/- mice compared to controls. Surprisingly, analysis of 4- and 14-month-old Grn-/- mice showed that clearance of phagocytosed photoreceptor outer segments proceeded normally, suggesting normal lysosome function. However, live imaging of mitochondrial dynamics in 4-month-old mouse RPE flatmounts revealed hyperfused mitochondria defective in ATP production. These hyperfused mitochondria activate NFkB, leading to increased secretion of the biologically active complement C3 fragment, C3a. This in turn activates C3aR on microglia subsequently triggering microglia migration and activation. Supporting this, RNA-sequence analyses of Grn-/- mice RPE reveal an upregulation of complement and inflammatory cascade signaling.
Conclusions :
Our data show that RPE mitochondrial deficits are an early pathological trigger in in Grn-/- mice. This activates C3aR signaling on maladaptive microglia, leading to photoreceptor degeneration. C3aR represents a potential target for GRN-FTD therapy.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.