Retinal degeneration is the leading cause of incurable blindness worldwide and is characterised by progressive loss of light-sensing photoreceptors in the neural retina. SARM1 is known for its role in axonal degeneration, but a role for SARM1 in photoreceptor cell degeneration has not been reported. SARM1 is known to mediate neuronal cell degeneration through depletion of essential metabolite NAD and induction of energy crisis. Here, we demonstrate that SARM1 is expressed in photoreceptors, and using retinal tissue explant, we confirm that activation of SARM1 causes destruction of NAD pools in the photoreceptor layer. Through generation of rho−/−sarm1−/− double knockout mice, we demonstrate that genetic deletion of SARM1 promotes both rod and cone photoreceptor cell survival in the rhodopsin knockout (rho−/−) mouse model of photoreceptor degeneration. Finally, we demonstrate that SARM1 deficiency preserves cone visual function in the surviving photoreceptors when assayed by electroretinography. Overall, our data indicate that endogenous SARM1 has the capacity to consume NAD in photoreceptor cells and identifies a previously unappreciated role for SARM1-dependent cell death in photoreceptor cell degeneration.

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 brain have shown that SARM1 plays a role in induction of neuronal axon degeneration in response to a variety of injuries. We recently demonstrated that SARM1 is pro-degenerative in a genetic model of inherited retinopathy. This current study aimed to characterise the effect of SARM1 deletion in an alternative model of retinal degeneration (RD) in which the retinal pigment epithelium (RPE) fragments following administration of oxidising agent, sodium iodate (NaIO3), leading to subsequent photoreceptor cell death. Following administration of NaIO3, we observed no apparent difference in rate of loss of RPE integrity in SARM1 deficient mice compared to WT counterparts. However, despite no differences in RPE degeneration, photoreceptor cell number and retinal thickness were increased in Sarm1–/– mice compared to WT counterparts. This apparent protection of the photoreceptors in SARM1 deficient mice is supported by an observed decrease in pro-apoptotic caspase-3 in the photoreceptor layer of Sarm1–/– mice compared to WT. Together these data indicate a pro-degenerative role for SARM1 in the photoreceptors, but not in the RPE, in an oxidative stress induced model of retinal degeneration consistent with its known degenerative role in neurons in a range of neurodegenerative settings.

The metallome has been involved in the pathological investigation into ocular tissue for decades; however, as technologies advance, more information can be ascertained from individual tissue sections that were not previously possible. Herein, a demonstration of complementary techniques has been utilized to describe the distribution and concentrations of essential metals in both wildtype (WT) and rhodopsin (Rho−/−) ocular tissues. The multimodal approach described is an example of complementary datasets that can be produced when employing a multifaceted analytical approach. Heterogenous distributions of copper and zinc were observable within both WT and Rho−/− tissue by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), and the distributions of further trace elements notoriously problematic for ICP-MS analysis (phosphorous, Sulfur, chlorine, potassium, calcium, iron, and aluminum) were analysed by particle-induced X-ray emission (PIXE).