Multi-disciplinary work led by researchers from Trinity College Dublin has reportedly pinpointed a potential new therapeutic target for treating retinal degeneration. The work has discovered that a protein (SARM1) involved in neuronal cell injury may also have a role in the progression of retinal degeneration.

The research “SARM1 deficiency promotes rod and cone photoreceptor cell survival in a model of retinal degeneration”, involving experts from Trinity’s Schools of Medicine, Biochemistry and Immunology, Genetics and Microbiology, and Engineering, has just been published in the journal Life Science Alliance.

Millions of people worldwide suffer varying degrees of vision-loss due to irreversible retinal degenerative diseases. In Ireland alone, approximately 5,000 people are affected by inherited retinal degenerations, while another 80,000 are known to live with age-related macular degeneration (AMD). Photoreceptor cells are specialized neurons found in the back of our eyes that convert light into electrical signals that allow us to see. It is the death of these cells, and the cells that nourish them, that is termed retinal degeneration and is characteristic of blinding diseases such as AMD and retinitis pigmentosa.

“Lots of different factors can initiate retinal degeneration and lead to severe visual impairment and eventual blindness, but ultimately the end-point is photoreceptor cell death,” Ema Ozaki, PhD, research fellow in clinical medicine at Trinity. “Although it seems unlikely the process of cell-death is, in fact, a programmed or organized event that directs proteins in our cells to take on ‘executioner’ roles.”

In this research, the team led by Sarah Doyle, PhD, assistant professor in immunology at Trinity, investigated the role of one such “executioner protein” called SARM1. The protein has come to the fore recently in the study of brain and spinal injury, as it is highly efficient at triggering the degeneration of neuronal cells. While the retina is an extension of the brain, this report is the first to describe a role for SARM1 in photoreceptor cell biology.

“Retinal degeneration is the leading cause of incurable blindness worldwide and is characterized 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,” write the investigators.

“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.”

“Our research indicates that SARM1 is likely to be a key executioner in the process of retinal degeneration, because if we remove it from our experimental model system this has the effect of delaying the photoreceptor cells from dying,” explained Doyle. “This is an important finding because the first steps involved in processing ‘light into sight’ take place in the photoreceptors. As a result, losing photoreceptors ultimately equates to losing vision. For this reason, interventions that prevent or delay photoreceptor cell death are critical to preserve sight for as long as possible in people with degenerative retinal diseases.”

The research team was also able to show that the protected and surviving photoreceptors maintained their function and continued to transmit electrical signals to the optic nerve. This research has therefore provided a new therapeutic target to slow the progression of blinding diseases.

“This is particularly exciting for the future because others have recently shown that a gene therapy approach for inhibiting SARM1 is effective in protecting against neuronal degeneration,” added Doyle. “We know that gene therapy is well suited as a treatment for retinal disease, so such an approach for inhibiting SARM1 activity may offer an option for protecting vision across multiple retinal degenerative diseases.”

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