Researchers have discovered that failing to dispose of old photoreceptor cells leads to age-related macular degeneration.
The estimated number of people worldwide with age-related macular degeneration in 2020 was 196 million, increasing to 288 million in 2040. Though more than 50 genes are associated with the condition, the precise mechanism is unknown. Most people have a form of the condition, for which there are no known effective treatments.
In order to develop new therapies to treat the disease, University of Maryland School of Medicine (UMSOM) researchers are starting to understand what goes wrong in the disease. Using human and mice tissue, researchers showed that the process which removes the eye’s old, damaged light sensors is disrupted in macular degeneration.
Previously, the lead researcher had found out that many families with hearing disorders had genetic mutations in the gene for the CIB2 protein, and later work also showed that CIB2 was needed for vision in a large human family, as well as in zebrafish. Now, in this latest study, his team built on that previous work to dissect the intricate cell mechanisms behind retinal degeneration.
The team compared healthy mouse eyes to those from a mouse with the CIB2 protein genetically deleted. These CIB2 mutant mice were not disposing of their old light sensor proteins, called photoreceptors, like healthy mouse eyes did.
“Photoreceptors continue growing in tiny columns in the eye, but over time, light damages the photoreceptors. To combat this, support cells in the eye slowly munch on the old, damaged photoreceptors, keeping the columns the correct length,” explained first author Saumil Sethna, PhD, at the University of Maryland School of Medicine. “If the photoreceptors are not removed, or if the process is backed up due to slow digestion by the support cells, like in the CIB2 mutant mice, the undigested material builds up over time, which may contribute to blindness.”
The researchers then identified several components in this photoreceptor recycling process, including a group of proteins collectively called mTORC1, which is involved in many human diseases, including cancer, obesity, and epilepsy.
Since mTORC1 (part of a family called mTOR) is a decision-maker for many cellular functions including cleaning up cellular debris, the researchers examined mTORC1’s activity in the CIB2 mutant mice and saw that it was overactive. mTORC1 was also found to be overactive in eye tissue of people with a form of age-related macular degeneration. The findings therefore indicate that drugs against mTORC1 may be effective treatments for the most common type of age-related macular degeneration, according to the researcher.
“Researchers have tested many small molecules directed at mTORC1 to treat various diseases, but the problem is that mTOR is needed for so many other cell functions that there are major side-effects when you tinker with it,” said senior author Zubair M Ahmed, PhD, Professor of Otorhinolaryngology-Head & Neck Surgery and Ophthalmology at the University of Maryland School of Medicine. “In our study, we found a backdoor way to regulate mTORC1, which may bypass many of the unpleasant side-effects that normally occur with suppressing mTORC1. We think we may be able to use our new knowledge of this mechanism to develop treatments for age-related macular degeneration and other diseases as well.”
