New study on gene modulation may help prevent blindness

Genes borrowed from a spider turned Peter Parker into Spiderman. If scientists can use archaea--tiny organisms similar to bacteria--as a source of useful genes for humans, might it help prevent blindness one day?

West Virginia University researcher Maxim Sokolov and his colleagues have received $1.5 million from the National Institutes of Health to study the biochemistry that might make it possible.

I recently watched Spiderman again," Sokolov said. "Remember, in Spiderman, Peter Parker was bitten by a spider, the spider gave him some of its DNA and he got the traits he didn't have before. We had the same idea."

Maxim Sokolov, researcher, West Virginia University

Only instead of combining spider and human DNA, Sokolov and his team--including WVU researcher David Smith--will add archaeal DNA to mouse models' genes. Then they'll assess whether the mouse models gain the "superpower" of resisting retinal degeneration.

Archaea are microscopic, single-celled organisms that populate diverse habitats, from the hydrothermal waters of Yellowstone National Park to our very own guts. Unlike mammals and other complex life forms, archaea produce special proteins in their cells--called molecular chaperones--that help them to survive in the harsh environment.

"Generally speaking, molecular chaperones guide other proteins through the folding process. They embrace the baby proteins and help them to fold correctly," said Sokolov, an associate professor in the School of Medicine's Departments of Ophthalmology and Visual Sciences, Biochemistry and Neuroscience. "And if the baby proteins fold incorrectly, the chaperones will unfold them and say, 'Fold again.'" In this sense, they act like "janitors" that purge the cells of aberrant proteins.

Avoiding and getting rid of misfolded proteins is crucial. If they accumulate in a cell, they can lead to serious problems. Specifically, a pileup of misfolded proteins in our eyes' photoreceptors, due to certain mutations, will slowly kill the photoreceptors and cause blindness.

To counteract these effects, Sokolov and his team will use archaeal genes to instruct cells to make archaeal molecular chaperones. According to the researchers' earlier work, doing so will prompt mouse cells to produce chaperones they would never make naturally.

"You bypass evolution," Sokolov said. "All of a sudden, this chaperone that's not present in mammals--not just mice but mammals--is there. But you don't know what will happen. This is where you start to do research."

The team will determine if--and how--the archaeal chaperones protect the mouse models' photoreceptors from the harmful effects of misfolded proteins. They'll also investigate how well the intervention thwarts retinal degeneration caused by several mutations linked to the development of blindness in humans.

What they discover could suggest new methods to prevent incurable eye diseases, including retinitis pigmentosa, a genetic disorder that causes irreversible vision loss. But their findings may also have broader implications.

After all, proteins can be misfolded in any cell. Folding errors are particularly harmful for the nervous system, where the buildup of misfolded proteins has been observed in a range of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases.

"There are diseases in the brain, and there is this disease called aging" said Sokolov. "We've used the eye as the model, but I'll be interested to look much, much wider than that."

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