Advances in understanding the mechanisms of retinal degenerations

Photoreceptor death is an important contributor to irreversible vision loss worldwide. In this review, I outline our work examining the role that purines, such as adenosine triphosphate (ATP), have in normal retinal function and in retinal disease. Our work shows that the actions of ATP, mediated by P2X receptors, are expressed in various retinal layers including photoreceptor terminals, and when stimulated by excessive levels of ATP is associated with rapid death of neurons. Treatment with a compound that blocks the action of P2X and some P2Y receptors reduces photoreceptor death in a mouse model of retinal degeneration. Our observations not only provide a means for developing a potential treatment for reducing photoreceptor death, but also provides a novel way of studying the neural plasticity effects that develop in the inner retina following photoreceptor death. There are a range of inner retinal changes that could influence the effectiveness of retinal prostheses. Indeed, using an ATP-induced degeneration model, we established that the amount of electrical stimulation required to elicit a response in the visual cortex was affected by the level of glial scarring. However, changes in P2X7 receptor expression by OFF ganglion cells during retinal degeneration can also be exploited by photoswitches to restore light sensitivity to degenerated retinae. Finally, our work has also considered how P2X7 expression by innate immune cells, and its role as a scavenger receptor, contributes to age-related macular degeneration (AMD). Our results show that loss of P2X7 function is associated with thickening of Bruch's membrane as well as increased risk of advanced disease in people with AMD. Overall, our work over the last 20 years highlights the importance of purinergic signalling in normal retinal function and retinal disease and suggest that developing therapies that target P2X7 function could be of benefit for these diseases.