OSU research helps shed light on cell death in ALS, other diseases
Researchers at Oregon State University and other institutions have identified key elements common to a number of degenerative diseases that could serve as targets for more effective treatment.
A study published Monday in the journal Proceedings of the National Academy of Sciences shows how a widespread cellular protein, HSP90, can become toxic after being attacked by free radicals in the body.
HSP90 is important to normal cell function, but through a process called tyrosine nitration, it can turn from helpful to harmful, triggering inflammation that can lead to a host of serious ailments from heart disease to cancer and amyotrophic lateral sclerosis, commonly known as ALS or Lou Gehrig’s disease.
The study also demonstrated that a protein receptor called P2X7 plays a crucial role in HSP90 toxicity and its effect on motor neurons, which control muscle function.
Together, those two findings could open the door to better therapies for some of the most devastating diseases afflicting mankind.
Joseph Beckman, a principal investigator at OSU’s Linus Pauling Institute and one of the study’s authors, said the research points to possible new uses for a class of drugs developed in recent years that target P2X7.
Those drugs are intended for treating arthritis and pain management, but the study’s findings suggest they could also be helpful in treating ALS, a focal point of Beckman’s research at the Linus Pauling Institute.
“Now we’re getting closer and closer to finding new ways of treating it,” he said. “And not just ALS — this process is involved in a lot of different disease processes.”
Parkinson’s disease, Alzheimer’s and possibly even spinal injuries could be treated using drugs that bind to P2X7, Beckman said.
There are also pharmaceuticals that target HSP90. Because that protein is involved in a complex web of essential bodily processes, those drugs can have severe side effects. The new research could allow drug developers to refine their formulas to target only the dangerous, nitrated form of HSP90.
“You can make (a drug) that’s much more selective,” Beckman said.
The study, titled “Nitration of HSP90 Induces Cell Death,” was unusually complex and collaborative, involving 18 scientists at eight institutions in the United States and Spain. Several besides Beckman have OSU connections.
Lead author Alvaro Estevez and senior author Maria Clara Franco, both now at the University of Central Florida, previously worked at the Linus Pauling Institute. Ryan Mehl, an associate professor of biochemistry and biophysics at the Corvallis campus, and Timothy Rhoads, who recently completed a doctorate there, are co-authors.
The study’s real breakthrough, Beckman said, lies in the development of a whole new set of methods for pinning down critical links in oxidative stress, which occurs when free radicals break down healthy cells.
“If you really understand the mechanism of what causes the disease, it helps focus the research,” he said. “Right now people are dancing around in the dark, trying to figure out what part of the elephant they’re holding.”
While much more work is needed before new drugs that target nitrated HSP90 or P2X7 are ready for use in humans, Beckman stressed, “we’re light years ahead of where we were.”