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Yale Researchers Find That Ubiquitous Cellular Protein, Polycystin 2, When Unmutated, Plays Lead Role In Cell Survival; When Mutated, It Can Cause Polycystic Kidney Disease (PKD)

The protein known as polycystin 2 is present in every cell in the body, but, until now, scientists knew little about its purpose. Yale researchers; together with colleagues at the University of Illinois at Urbana, the Washington University School of Medicine in St. Louis, and Heidelberg University; have discovered that it protects against cell death, making it a potential target for therapies to treat a variety of diseases of the liver and kidneys, as well as for brain aneurysms, heart disease, and cancer. Polycystin 2 (PC2 or TRPP1, formerly TRPP2) is a calcium-permeant transient receptor potential (TRP) cation channel expressed primarily on the endoplasmic reticulum (ER) membrane and primary cilia of all cell and tissue types. The new research on polycystin 2 was reported online on January 15, 2020 in Scientific Reports. The open-access article is titled “Polycystin 2 Is Increased in Disease to Protect Against Stress-Induced Cell Death.” There are over 6 million protein species in the human body, and scientists are still learning the key roles these proteins play. In the case of polycystin 2, researchers had almost exclusively focused on the protein’s role in polycystic kidney disease (PKD), specifically autosomal dominant PKD (AD-PKD), from which the protein draws its name. When polycystin 2 is mutated, it triggers the disease, which is characterized particularly by the development of large, fluid-filled cysts in the kidney, causing renal failure that necessitates a kidney transplant. “No one knew any function for this protein other than when it was mutated,” said Barbara Ehrlich (at left in photo), PhD, Yale Professor of Pharmacology and of Cellular and Molecular Physiology, who co-led the study with graduate student Allison Brill (at right in photo), 2020 Yale Graduate School of Arts & Sciences (GSAS). Brill had earned her BS at the University of Wisconsin-Madison, where she focused on the study of high fat diet-induced type 2 diabetes.

The researchers found that polycystin 2 levels increase in response to disease-driven cell stress in multiple tissue types, including the kidney, liver, brain, and heart of both human and animal models. They also showed that when the protein was removed from tissues, cells were more sensitive to stress and susceptible to cell death. In short, the research showed that polycystin 2 plays an important function in cell survival.

“A lot of diseases involve abnormal response to stress and a rise in cell death,” said Brill.

For the study, researchers looked at levels of polycystin 2 in human kidneys with acute kidney injury; in human livers with non-alcoholic fatty liver disease; in human hearts following cardiac disease; and in human brains following epilepsy. In all cases, polycystin 2 levels rose in response to disease-related cell stress.

The finding is an important step on the path to a full understanding of the role this protein plays, and how it can be targeted to treat disease, said the researchers.

“Now we want to know what changes in the cell when polycystin 2 levels increase,” said Dr. Ehrlich. “One of the components of the pathway related to this protein may be an ideal target for a drug.”

In some cases, these diseases have few promising treatment options.

The researchers note, for instance, that the only treatment currently available for polycystic kidney disease has a severe diuretic side effect that requires patients to drink over two gallons of water a day.

“Because polycystin 2 was found to increase in all these tissues, there are a lot of avenues to explore,” Brill said.

Yale researchers who contributed to this study include: Marie Robert, MD, Professor of Pathology and of Medicine (digestive diseases); Gilbert Moeckel, MD, Professor of Pathology; Lloyd G. Cantley, MD, the C.N.H. Long Professor of Medicine (nephrology) and Professor of Cellular and Molecular Physiology; Stuart Campbell, Associate Professor; Tom T. Fischer, PhD, Postgraduate Fellow; Arnaud Marlier, Associate Research Scientist; and Lorenzo Sewanan, MD/PhD student.

This post was prepared on the basis of a Yale News article written by Brita Belli and published on February 5, 2020.

[Yale News article] [Scientific Reports article]

IMAGES

At left, Dr. Barbara Ehrlich (l) is shown with graduate student Allison Brill. At right, polycystic kidney (l) is shown in comparison with normal kidney.