Retinal degeneration is a characteristic of neurodegenerative diseases such as age-related macular degeneration (AMD) or retinitis pigmentosa and can lead to severe visual impairment and eventual blindness. There are a wide range of factors that can initiate retinal degeneration, but ultimately the end-point is photoreceptor cell death. Identifying unifying pro-death or pro-survival mechanisms in these diseases has the potential to offer global therapeutic approaches for facilitating the protection of visual function across multiple diseases. SARM1 is a member of the Toll/IL-1Receptor (TIR) domain-containing superfamily and can regulate innate immune activation. SARM1-mediated cell death is a recently described pro-degenerative programme prominent in the central nervous system (CNS). Endogenous SARM1 promotes neuronal cell death in response to a wide range of disparate insults, including oxidative stressors. Of note, smoking is the largest modifiable risk factor for AMD, and consequently, excessive oxidative stress, has been implicated in this disease. The retina is an extension of the CNS, however, a role for SARM1 in mediating RPE or photoreceptor cell-death has not been reported representing a significant gap in our knowledge. In this research proposal, we aim to characterise the role of SARM1, a pro-degenerative executioner molecule, in the retina, both in the absence of injury and in response to oxidative stress. Activation of SARM1 leads to a precipitous loss in the metabolite NAD+ triggering a metabolic crisis that is highly effective in triggering cell-death both in neuronal cells. Our preliminary data leads us to hypothesize that SARM1 plays a role in mediating RPE and photoreceptor cell-death, potentially through NAD+ depletion. Data generated has the potential to provide a new therapeutic target to slow the progression of blinding diseases. This is particularly exciting, as development of inhibitors of SARM are already underway for neurodegenerative diseases of the CNS.