Study on ground squirrels points to possible development of a drug against cataracts

Researchers at the National Institutes of Health (NIH) and their collaborators have identified a protein called RNF114 that reverses cataracts, a clouding of the lens of the eye that is common in people as they age. The study, conducted on three-lined ground squirrels and rats, may represent a potential strategy for treating cataracts without surgery, a common cause of vision loss. The Journal of Clinical Investigations.

“Scientists have long sought an alternative to cataract surgery that is effective but not without risk. Lack of access to cataract surgery is a barrier to treatment in some parts of the world, resulting in untreated cataracts being a leading cause of blindness worldwide,” said Dr. Xingchao Shentu, a cataract surgeon and co-lead researcher at Zhejiang University in China.

This new discovery was part of ongoing research at the NIH's National Eye Institute (NEI) involving a hibernating mammal, the thirteen-lined ground squirrel. In these ground squirrels, the light-sensitive photoreceptor cells in the retina are mostly made up of cones, making the ground squirrel useful for studying cone-related properties such as color vision. In addition, the ground squirrel's ability to survive months of cold and metabolic stress during hibernation makes it a model for vision researchers to study a range of eye diseases.

The researchers found that the ground squirrels' lenses became cloudy during hibernation at about 4 degrees Celsius, but quickly became clear again after rewarming. In comparison, non-hibernators (rats in this study) developed cataracts at low temperatures, but these did not improve upon rewarming.

Cataract formation in hibernating animals exposed to cold temperatures is likely a cellular response to cold stress and one of many changes their bodies undergo as their tissues adapt to freezing temperatures and metabolic stress. Humans do not develop cataracts in cold temperatures.

“Understanding the molecular causes of this reversible cataract phenomenon may point us in the direction of a potential treatment strategy,” said study co-leader Wei Li, Ph.D., senior investigator in the NEI's Division of Retinal Neurophysiology.

The lens's main job is to focus light onto the retina at the back of the eye. As we age, cataracts form when proteins in the lens begin to fold incorrectly, forming clusters that block, scatter, and distort light as it passes through the lens. For reasons unclear, aging can disrupt protein homeostasis – a process that maintains the balance between newly formed proteins and the replacement of old ones.

To study the ground squirrel's reversible cataract at the molecular level, the team developed a lab-based lens model in a dish using stem cells grown from ground squirrel cells by the Li Lab at NEI. Using this platform, the researchers focused on one part of an extensive network that maintains protein homeostasis in part by degrading old proteins, known as the ubiquitin-proteasome system.

Notably, RNF114 levels were significantly increased in the ground squirrel during rewarming compared to the non-hibernating rat. RNF114 has previously been shown to help identify old proteins and facilitate their degradation.

To further investigate the effect of RNF114, they again used a non-hibernating cataract model (rat) whose lenses were incubated at 4 degrees Celsius. Normally, such a cataract would not resolve upon reheating. However, when the lenses were pretreated with RNF114, reheating resulted in rapid healing of the cataract.

According to the team of scientists, these results are proof that it is possible to induce cataract healing in animals. In future studies, the process needs to be refined so that scientists can stimulate the degradation of specific proteins to find out how to precisely regulate protein stability and turnover. This mechanism is also an important factor in many neurodegenerative diseases, they said.