In addition to genetic alterations, environment plays a role. Understanding them will lead to treatment
In a significant finding, scientists have identified two molecular level mechanisms that lead to glaucoma, the fourth main cause of blindness in India.
Glaucoma is a slowly progressing disease and is more prevalent in the elderly. Besides old age, several risk factors cause it — family history, ethnic background, high intra-ocular pressure and high blood pressure. Long-term usage of steroids could also cause the disease.
Unlike in cataract, which is the leading cause for blindness, loss of vision caused by glaucoma cannot be regained by therapeutic intervention, said Dr. Ghanshyam Swarup, scientist from the Hyderabad-based Centre for Cellular and Molecular Biology (CCMB), who studied the molecular mechanism of glaucoma in collaboration with L.V. Prasad Eye Institute, Hyderabad.
Observing that mutations in certain genes are primarily responsible for glaucoma, Dr. Swarup said that in addition to genetic alterations, environmental factors too contribute. One of the mutated genes causing glaucoma was OPTN which codes for protein optineurin. An alteration in this gene (M98K) was earlier associated with glaucoma only in South Asian population.
OPTN was one of the genes associated with glaucoma where intra-ocular pressure was not involved. According to Dr. Subhabrata Chakrabarti, Associate Director of L.V. Prasad Eye Institute, the gene was studied in detail as the molecular mechanism of how it causes glaucoma was not known.
Understanding the molecular mechanism would go a long way in devising strategies for treating and preventing further damage.
“We have [now] determined the mechanism of how this alteration causes the disease,” Dr. Swarup noted. “The alteration induces cell death in retinal ganglion cells.”
However, the mutation affected only the retinal ganglion cells and not other neuronal and non-neuronal cells. So by arresting ganglion cell death, further damage can be arrested and residual vision saved even after the onset of glaucoma.
It was found that the cell death occurs due to enhanced autophagy (the process that removes damaged proteins and organelles in the cells by degradation). Any change in this — either increase or decrease — could lead to cell death.
Dr. Swarup said the work also enhanced the understanding of the process of autophagy, which was essential to maintain healthy cells.
For instance, the scientists were able to stop cell death by blocking the enhanced activity of autophagy using chemical inhibitors.
He said they were currently studying the role of optineurin in transporting materials like proteins and lipids from one cell compartment to another within the same cell (membrane vesicle trafficking) and in signalling involved in gene expression.
“Our work showed that regulating one of the trafficking processes known as endocytic recycling was fundamental to the uptake of iron by the cell,” he noted. A mutation in optineurin (E50K) causes a defect in endocytic recyling and leads to death of retinal ganglion cells.
Dr. Swarup said that their work would help in devising a therapeutic strategy to prevent cell death caused by mutation.