Abstract
Purpose :
SARM1 (sterile alpha and armadillo motif-containing protein) is a highly conserved Toll/IL-1 Receptor (TIR) adaptor with important roles in mediating immune responses. Studies in the CNS have shown that SARM1 plays a role in induction of neuronal axon degeneration in response to a variety of injuries. Activated SARM1 consumes essential metabolite NAD+ leading to cellular metabolic catastrophe and axon degeneration. Retinal degenerative diseases (RDDs), such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD), are leading causes of incurable blindness and share a common endpoint, the degeneration of specialized neurons; photoreceptor cells. We sought to investigate whether SARM1 serves a pro-degenerative function during photoreceptor cell degeneration in models of RDD.
Methods :
Using models of photoreceptor (Rho-/- mice) and RPE (intravenous administration of sodium iodate) degeneration we investigated the role of SARM1 during retinal degeneration, by generation of Rho-/-Sarm1-/- mice and use of Sarm1-/- mice respectively. We performed ocular coherence tomography (OCT), electroretinography (ERG) and histological analysis of retinal tissue sections to characterize the extent of retinal degeneration in these models in the absence of SARM1. We performed fluorescence lifetime imaging microscopy (FLIM) on retinal explant tissue to measure the levels of NADH in the Rho-/-model in the presence of absence of SARM1.
Results :
In both models Sarm1 deficiency delayed retinal degeneration, preserving photoreceptor cells as assessed by both OCT and hematoxylin & eosin staining of tissue sections. In Rho-/- mice there is reduced NADH levels at 4 weeks of age, this is in contrast to Rho-/-Sarm1-/- mice where NADH pools are maintained. As NADH exists in a relationship with NAD+ we can infer that SARM1 is cleaving NAD+ during retinal degeneration in this model. ERG analysis demonstrates preserved function of photoreceptor cones in the RDD models in the Sarm1-/- mice, indicating that the preserved photoreceptor cells are viable and retain light sensitivity for a visual response.
Conclusions :
Our present data identifies a previously unappreciated role for SARM1 in photoreceptor cell death but not RPE cell death. SARM1 serves a distinct function in the course of photoreceptor degeneration to its previously described role in other neuronal cell types mediating cell death in addition to axon degeneration.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.