Rochester University researcher awarded 2017 Shaffer Prize
Cells follow pathway
Retinal ganglion cells, like other cells in the body, live and die by following specific molecular pathways. These pathways cascade from one step to the next.
By working up the cascade from any starting point, it is possible to understand what causes a particular molecule, such as SARM1, to become active. Working down the cascade shows what that same molecule causes to happen later in the pathway. Working through the cascade, step by step, can be a slow process.
Dr. Libby said it has been clear for some time that one way to control glaucoma is to block the cascade that leads to axonal injury, axonal degeneration, and retinal ganglion cell death. It was recognized that axonal injury is an early and important event in the development of glaucoma.
However, no one knew how axonal degeneration progressed. The identification of SARM1’s role in retinal ganglion cell axonal degeneration is an early step in determining the degeneration cascade that leads from axonal injury to vision loss in glaucoma.
“When we removed SARM1, we significantly delayed axonal degeneration,” Dr. Libby said. “That suggests it plays an active role in causing, or least in promoting, axonal degeneration. The next step is to figure out what turns that molecule on.”
The pathways that guide and direct axonal degeneration were all but unknown 10 years ago and are slowly becoming understood. Because removing SARM1 appears to reduce axonal degradation and protect against the development of glaucoma, finding a way to block one or more steps in the pathway leading to axonal death offers the promise of neuroprotection. Inhibiting SARM1 or inhibiting earlier steps in the pathway that lead to SARM1 could become a powerful therapeutic approach to treating glaucoma.
It is still too early to talk about a specific therapy, Dr. Libby said. But for the first time, there is the clear potential for a treatment that could directly slow or even stop the axonal damage that leads to glaucoma.
“The real key is that we are starting to define the endogenous molecules inside axons that are critical for degradation,” he said. “It is a first step in understanding and stopping the axonal degradation cascade in glaucoma. We have to understand that cascade in order to get at the heart of the disease and rationally design a treatment that goes to the nerve degeneration that results in glaucoma.”