Researchers at the National Institutes of Health (NIH) and Zhejiang University have identified the RNF114 protein as a key factor in reversing cataracts in animal models, suggesting a potential non-surgical treatment strategy for this common age-related condition. The study, published in the Journal of Clinical Investigation, offers a promising avenue for developing a cataract drug, addressing a significant unmet need in global eye care.
Reversible Cataracts in Hibernators
The discovery stemmed from ongoing research at the NIH's National Eye Institute (NEI), which focused on the 13-lined ground squirrel, a mammalian hibernator. Scientists observed that the lenses of these squirrels became cloudy at low temperatures (around 4 degrees Celsius) during hibernation but regained transparency upon rewarming. In contrast, non-hibernating rats developed cataracts at similar temperatures, but these did not resolve with rewarming.
Wei Li, Ph.D., senior investigator in the NEI Retinal Neurophysiology Section and co-lead investigator, noted, "Understanding the molecular drivers of this reversible cataract phenomenon might point us in a direction toward a potential treatment strategy."
RNF114's Role in Protein Homeostasis
Cataracts typically form when proteins in the lens misfold and aggregate, scattering light and impairing vision. This process is often linked to a disruption in protein homeostasis, the balance between protein synthesis and degradation. The researchers found that RNF114, a protein involved in the ubiquitin proteasome system (which breaks down old proteins), was significantly elevated during rewarming in the ground squirrel lenses.
Inducing Cataract Clearance
To further investigate RNF114's effect, the researchers incubated rat lenses at 4 degrees Celsius to induce cataract formation. Normally, these cataracts would not resolve upon rewarming. However, when the lenses were pretreated with RNF114, a rapid clearing of the cataract was observed upon rewarming.
Implications for Cataract Treatment
Xingchao Shentu, M.D., a cataract surgeon and the co-lead investigator from Zhejiang University, China, emphasized the global need for alternative treatments: "Scientists have long searched for an alternative to cataract surgery, which is effective, but not without risk. Lack of access to cataract surgery is a barrier to care in some parts of the world, causing untreated cataracts to be a leading cause of blindness worldwide."
The research team believes these findings provide proof-of-principle that cataract clearance can be induced in animals. Future studies will focus on fine-tuning the process to stimulate specific protein degradation, precisely regulating protein stability and turnover. This mechanism is also relevant to many neurodegenerative diseases, suggesting broader implications for RNF114 research.
