Research points to new way to prevent optic nerve degeneration in glaucoma

| Written by Jessica Moore
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Over 3 million Americans have glaucoma, the group of eye diseases that damage the nerve that carries information from the eye to the brain. This damage slowly degrades patients’ vision, even with treatment. Current glaucoma drugs lower the pressure in the eye, which lessens the injury to the nerve, although it is not eliminated. Finding ways to protect the optic nerve could lead to treatments that are much more effective in preserving or restoring sight in glaucoma patients.

An exciting advance toward this goal builds on the discoveries of SBP’s Randal J. Kaufman, Ph.D., professor and director of the Degenerative Diseases Program. The study to which he contributed, published in the Journal of Neuroscience and led by Yang Hu, M.D., Ph.D., at the Temple University School of Medicine, identifies new potential therapeutic targets for glaucoma.

These targets are part of the pathway that Kaufman has spent his career unraveling—the response to buildup of too many proteins in the endoplasmic reticulum (ER), the part of the cell where proteins are folded into their intended, functional shape. This condition, called ER stress, arises in the early stages of glaucoma in the cells that make up the optic nerve. If ER stress is prolonged, these cells stop sending signals and eventually die.

The new paper shows how to manipulate the response to ER stress, called the unfolded protein response (UPR), to protect the optic nerve. The UPR involves multiple events—one enhances protein-folding capacity and breakdown of ER-clogging proteins, and another triggers cell death (protecting surrounding cells from possible damage by the stressed cells).

Hu’s team used a mouse model of glaucoma in which pressure inside the eye is artificially increased. They found that activating the response that fixes the problems with the ER and inhibiting the response that leads to cell death enhances survival of the cells that make up the optic nerve.

“The important result here is that these manipulations preserved visual function,” said Kaufman. “That finding suggests that if we could find drugs that alter the UPR in the same way, they might help glaucoma patients retain their vision."

The paper is available online here.

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