Therapeutic Target Identified To Aid Glaucoma Treatment

Researchers from Indiana University School of Medicine have discovered a novel therapeutic target that might result in more successful glaucoma treatment.
A damaged optic nerve underlies the neurodegenerative illness glaucoma, which results in visual loss and eventual blindness. Glaucoma affects more than 200,000 persons in the United States annually. Regrettably, there is no cure at this time. Researchers discovered that neurons use mitochondria as a consistent source of energy in a recently published work in Communications Biology and that restoring mitochondrial homeostasis in sick neurons can shield the optic nerve cells from harm.

“Age-related neurodegenerative disease, which includes glaucoma, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS), is the biggest global health problem,” said Arupratan Das, Ph.D., assistant professor of ophthalmology and principal investigator of the study.

“The fundamental mechanisms that we discovered can be used to protect neurons in glaucoma and be tested for other diseases. We have identified a critical step of complex mitochondrial homeostasis process, which rejuvenates the dying neuron, similar to giving a lifeline to a dying person.”

The research team, led by Michelle Surma and Kavitha Anbarasu from the Department of Ophthalmology, used induced pluripotent stem cells (iPSCs) from glaucoma patients and those without the disease, as well as human embryonic stem cells modified to have the glaucoma mutation using clustered regularly interspaced short palindromic repeats (CRISPR).

Researchers found that glaucomatous retinal ganglion cells suffer from a mitochondrial deficit with a greater metabolic burden on each mitochondrion using stem cell-derived retinal ganglion cells (hRGCs) of the optic nerve, electron microscopy, and metabolic analyses. Degeneration and damage to the mitochondria result from this. Adenosine triphosphate, the energy supply for cells, is produced by mitochondria, the tube-like organelles in cells.

However, the process could be reversed by enhancing mitochondrial biogenesis by a pharmacological agent. The team showed retinal ganglion cells are highly efficient in degrading bad mitochondria, but at the same time producing more to maintain homeostasis.

“Finding that retinal ganglion cells with glaucoma produce more adenosine triphosphate even with less mitochondria was astonishing,” Das said. “However, when triggered to produce more mitochondria, the adenosine triphosphate production load was distributed among more mitochondrion which restored the organelle physiology. It is similar to a situation where a heavy stone is carried by fewer people versus a greater number of people—each person will have less pain and injury, just like each mitochondrion will have less difficulty and damage.”

In the future, Das would like to test if these mechanisms protect the optic nerve in animal models under injury before testing in humans to hopefully lead to new clinical interventions with respect to glaucoma treatment.

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