Discovery of 'executioner' protein opens door to new options for stroke ALS, spinal cord injury

Alvaro Estevez, an associate professor at the University of Central Florida's College of Medicine, led the multi-university team that made the discovery, which could eventually help scientists develop new therapies to combat a host of conditions from stroke to Lou Gehrig's disease.

Researchers have long known that oxidative stress damages cells and results in neurodegeneration, inflammation and aging. It was commonly believed that oxidation made a "crude," demolition-like attack on cells, causing them to crumble like a building in an earthquake, Estevez said. However, the latest findings show that oxidation results in a much more targeted attack to specific parts of the cell. Oxidative stress damages a specific "chaperone" cell protein called Hsp90. It plays a role in up to 200 different cell functions. But when a form of oxidative stress called tyrosine nitration modifies that protein, it turns into the cell "executioner" shutting it down.

"The concept that a protein that is normally protective and indispensable for cell survival and growth can turn into a killing machine, and just because of one specific oxidative modification, is amazing," said Maria C. Franco, a postdoctoral associate at UCF's Burnett School of Biomedical Sciences. She co-wrote the study. "Considering that this modified protein is present in a vast number of pathologies, it gives us hopes on finding new therapeutics approaches for several different diseases."

For example, researchers could devise a drug that stroke patients could take at the onset of their symptoms to prevent more healthy cells from dying, thus limiting the damage of the stroke. Because oxidation is linked to inflammation, researchers believe tyrosine nitration could also be related to other health problems including heart disease, cancer, aging and chronic pain.

"These are very exciting results and could begin a major shift in medicine," said Joseph Beckman, from Oregon State University Environmental Health Sciences Center, a collaborator on the study. "Preventing this process of tyrosine nitration may protect against a wide range of degenerative diseases."

"Most people think of things like heart disease, cancer, aging, liver disease, even the damage from spinal injury as completely different medical issues," Beckman said. "To the extent they can often be traced back to inflammatory processes that are caused by oxidative attack and cellular damage, they can be more similar than different. It could be possible to develop therapies with value against many seemingly different health problems."

Other contributors to the study include: Nicklaus A. Sparrow from UCF, Yaozu Ye from the University of Alabama at Birmingham, Christian A. Refakis, Jessica L. Feldman and Audrey L. Stokes from Franklin and Marshall College, Manuela Basso and Thong C. Ma from the Burke Medical Research Institute, Raquel M. Melero Fernández de Mera from Universidad de Castilla-La Mancha, Noel Y. Calingasan, Mahmoud Kiaei and M. Flint Beal from Weill Cornell Medical College, Timothy W. Rhoads, and Ryan Mehl from Oregon State University and Martin Grumet from Rutgers State University of New Jersey.

The National Institutes of Health, the Burke Medical Research Institute, the ALS Association and other agencies financially supported this study.

Estevez joined the UCF College of Medicine in 2010. Previously he worked as a postdoctoral investigator at the University of Alabama at Birmingham and then as an assistant professor. In 2005 Estevez joined the Burke Cornell Medical Research Institute a part of the Weill Cornell Medical College in New York. Estevez has several degrees including a doctorate in philosophy, biology and cell biology from the Instituto Clemente Estable in Montevideo Uruguay.