For patients with polycystic kidney disease (PKD), a common genetic disorder that ravages the waste-removing organ with cysts, dialysis and transplantation are among the only treatments.
More than 12.4 million people worldwide suffer from the dominant form of the condition. Now, Rutgers University geneticists have uncovered fresh details of how the disease progresses—findings that could open the door to new therapies.
In a study published in Nature Communications, Inna Nikonorova, a research assistant professor in the Department of Genetics within the Rutgers School of Arts and Sciences, reports on a novel way to identify and track material carried by extracellular vesicles (EVs)—sub-microscopic communication tools shed by cells that play a key role in the development of cancers, neurodegeneration and renal diseases such as PKD.
“Inna was able to identify the other proteins that travel with polycystic proteins inside EVs, proteins that no one really knew about before,” said Maureen Barr, a distinguished professor of genetics at Rutgers University-New Brunswick, and a co-author of the study. “For researchers in the PKD field, this is very exciting.”
Once considered a waste product of cells, researchers now understand the health implications of extracellular vesicles.
“Beneficial cargo within these transporters—proteins, for instance—aid in wound healing and tissue regeneration,” Nikonorova said. “But they can also function diabolically to spread toxic cargos and act as disease mediators.”
What has been unclear is how cargos are selected and packaged into extracellular vesicles.
To explore this mystery, Nikonorova and Barr zeroed in on an EV that carries PKD gene proteins and associated material. Changes to PKD proteins called polycystins are linked to disease progression.
Using findings from a previous study, Nikonorova developed a labeling tool to track the cargo of specialized EVs in a laboratory worm called C. elegans, which has a translucent body and rapid growth cycle. By deploying a green fluorescent protein that binds to polycystin-2, Nikonorova was able to watch the EV cargo travel through the body of the worm and map its interactions.
“Wherever the polycystins travel, you see a green light under the microscope,” she said. “It’s like giving someone a flashlight and watching them go room to room through a dark house.”
The tracking method Nikonorova used, known as “proximity labeling,” helped her determine the precise mechanism by which polycystins are packaged into EVs and the associated proteins that polycystins travel with throughout the body.
“We went beyond identification,” Nikonorova said.
Past studies have only named the proteins within EVs. By contrast, “We took each candidate and looked at whether it goes to vesicles with polycystins and interacts with them,” she said.
This information could help researchers understand what is happening within cells with missing polycystin proteins, essential knowledge for finding ways to cure polycystic kidney disease or slow its progression, Nikonorova said.
