Research Update

Researchers Identify Promising Target to Tackle Retinal Degeneration

Retinal degeneration is the leading cause of blindness worldwide which is characterised by the damage and death of the light-sensitive rod and cone cells (photoreceptor cells) in the retina. A multitude of common and rare diseases, such as Age-related Macular Degeneration and Retinitis Pigmentosa respectively are caused by retinal degeneration, and in many cases results in a progressive decline in visual acuity.

In normal vision, these rod and cone photoreceptor cells convert light signals to electrical signals and deliver them to the brain, where images are formed. Rod cells function in low light (scotopic vision) and have an important role in peripheral vision, while cone cells are most concentrated in the central region of the retina, known as the macula, to perceive bright light (photopic vision) and provide detailed central vision. Therefore, it is no surprise that people living with one or more forms of retinal degeneration experience a loss of peripheral vision, blind spots and blurred central vision.

Research published in Life Science Alliance has identified a new and potential therapeutic target for treating retinal degeneration, called SARM1¹. In this study, researchers from Trinity College Dublin discovered that the SARM1 protein, which is involved in the damage and destruction of neuronal cells; cells which transmit electrical signals through the body, may also have a role in accelerating retinal degeneration. Although the retina is an extension of the brain and thus part of the nervous system, this is the first study which describes SARM1 involvement in photoreceptor cell-death.

Using mice with normal vision, researchers identified SARM1 within the retina and retinal pigment epithelium cell-layer; an underlying layer which nourishes the rod and cone photoreceptor cells. Following on from this, researchers sought to understand the impact of SARM1 on NAD⁺ levels in the photoreceptor cells. NAD⁺ is an essential substance in the body which is required for proper metabolic function; the conversion of nutrients to energy and supporting cells with normal activity and survival.

NAD⁺ is known to be depleted in neuronal cells which are damaged and destroyed by SARM1, while a reduction in NAD⁺ stores has also been reported to precede photoreceptor degeneration in other animal models^2,3,4. Findings from this study are consistent with these reports and record a depletion in photoreceptor NAD⁺ levels, when SARM1 is present.

In light of these results, researchers created a mouse model of retinal degeneration to determine the effects of SARM1 on the rate of photoreceptor cell degeneration. To do this, the rhodopsin gene, which is commonly implicated in the onset of Retinitis Pigmentosa (RP) and involved in 20-30% of all cases of autosomal dominant RP, was inactivated or switched “off”⁵. Investigators compared the rate of rod and cone cell degeneration in mice with no rhodopsin or SARM1 protein present to mice who had no rhodopsin protein but continued to produce SARM1.

Over a 12 week period, it was discovered that mice with both the rhodopsin and SARM1genes inactivated experienced greater rod and cone photoreceptor cell survival compared to mice in which SARM1 activity was normal but had no rhodopsin protein.

The findings of this study are largely consistent with previous reports on SARM1 both in retinal research and elsewhere, and firmly indicate that inhibiting SARM1 activity within the retina will help to preserve rod and cone photoreceptor cell integrity. Delaying the rate of cell death will also provide more opportunities for successful treatment intervention, either as pharmacological or gene therapy, both of which are described as promising areas for research by the investigators.

References

1. Ozaki, E., Gibbons, L., Neto, N.G., Kenna, P., Carty, M., Humphries, M., Humphries, P., Campbell, M., Monaghan, M., Bowie, A. and Doyle, S.L., 2020. SARM1 deficiency promotes rod and cone photoreceptor cell survival in a model of retinal degeneration. Life Science Alliance, 3(5).
2. Gerdts, J., Brace, E.J., Sasaki, Y., DiAntonio, A. and Milbrandt, J., 2015. SARM1 activation triggers axon degeneration locally via NAD+ destruction. Science, 348(6233), pp.453-457.
3. Essuman, K., Summers, D.W., Sasaki, Y., Mao, X., DiAntonio, A. and Milbrandt, J., 2017. The SARM1 Toll/interleukin-1 receptor domain possesses intrinsic NAD+ cleavage activity that promotes pathological axonal degeneration. Neuron, 93(6), pp.1334-1343.
4. Liu, H.W., Smith, C.B., Schmidt, M.S., Cambronne, X.A., Cohen, M.S., Migaud, M.E., Brenner, C. and Goodman, R.H., 2018. Pharmacological bypass of NAD+ salvage pathway protects neurons from chemotherapy-induced degeneration. Proceedings of the National Academy of Sciences, 115(42), pp.10654-10659.
5. National Institute of Health. RHO gene. Available at https://ghr.nlm.nih.gov/gene/RHO#conditions. Accessed June 2020.