Discovery opens door to new drug options for serious diseases

March 4, 2013
A motor neuron can die when nitrated HSP90 binds to P2x7. Credit: Oregon State University

Researchers have discovered how oxidative stress can turn to the dark side a cellular protein that's usually benign, and make it become a powerful, unwanted accomplice in neuronal death.

This finding, reported today in , could ultimately lead to new therapeutic approaches to many of the world's debilitating or .

The research explains how one form of oxidative stress called tyrosine nitration can lead to cell death. Through the common link of inflammation, this may relate to health problems ranging from heart disease to chronic pain, spinal injury, cancer, aging, and amyotrophic lateral sclerosis, or Lou Gehrig's disease.

As part of the work, the scientists also identified a specific "chaperone" protein damaged by oxidants, which is getting activated in this spiral of cellular decline and death. This insight will provide a new approach to design .

The findings were published by scientists from the Linus Pauling Institute at Oregon State University; Maria Clara Franco and Alvaro Estevez, now at the University of Central Florida; and researchers from several other institutions. They culminate a decade of work.

"These are very exciting results and could begin a major shift in medicine," said Joseph Beckman.

Beckman is an LPI principal investigator, distinguished professor of biochemistry, and director of the OSU Center. He also last year received the Discovery Award from the Medical Research Foundation of Oregon, given to the leading medical scientist in the state.

"Preventing this process of tyrosine nitration may protect against a wide range of ," Beckman said. "The study shows that drugs could effectively target oxidatively-damaged proteins."

Scientists have known for decades about the general concept of oxidative damage to cells, resulting in neurodegeneration, inflammation and aging. But the latest findings prove that some molecules in a cell are thousands of times more sensitive to attack.

In this case, heat shock protein 90, or HSP90, helps monitor and chaperone as many as 200 necessary cell functions. But it can acquire a toxic function after nitration of a single tyrosine residue.

"It was difficult to believe that adding one nitro group to one protein will make it toxic enough to kill a motor neuron," Beckman said. "But nitration of HSP90 was shown to activate a pro-inflammatory receptor called P2X7. This begins a dangerous spiral that eventually leads to the death of motor neurons."

The very specificity of this attack, however, is part of what makes the new findings important. Drugs that could prevent or reduce oxidative attack on these most vulnerable sites in a cell might have value against a wide range of 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."

Beckman has spent much of his career studying the causes of amyotrophic lateral sclerosis, and this study suggested the processes outlined in this study might be relevant both to that disease and spinal cord injury.

Key to this research were new methods that allowed researchers to genetically engineer nitrotyrosine into HSP90. This allowed scientists to pin down the exact areas of damage, which may be important in the identification of drugs that could affect this process, the researchers said.

Explore further: Progression of Lou Gehrig's disease explained

Related Stories

Progression of Lou Gehrig's disease explained

October 17, 2011
Researchers in Uruguay and Oregon have discovered a previously unknown type of neural cell that appears to be closely linked to the progression of amytrophic lateral sclerosis, or Lou Gehrig's disease, that they believe will ...

Scientists define cellular pathway essential to removing damaged mitochondria

August 23, 2011
In a joint research effort with researchers at St. Jude Children's Research Hospital, and with help from scientists at The University of Pennsylvania, The University of Minnesota, and the National Institutes of Health, investigators ...

Scientists uncover potential drug target to block cell death in Parkinson's disease

January 10, 2013
Oxidative stress is a primary villain in a host of diseases that range from cancer and heart failure to Alzheimer's disease, Amyotrophic Lateral Sclerosis and Parkinson's disease. Now, scientists from the Florida campus of ...

Potential new drug target in Lou Gehrig's disease

November 14, 2011
Two proteins conspire to promote a lethal neurological disease, according to a study published online this week in the Journal of Experimental Medicine.

Recommended for you

New vaccine production could improve flu shot accuracy

July 24, 2017
A new way of producing the seasonal flu vaccine could speed up the process and provide better protection against infection.

Molecular hitchhiker on human protein signals tumors to self-destruct

July 24, 2017
Powerful molecules can hitch rides on a plentiful human protein and signal tumors to self-destruct, a team of Vanderbilt University engineers found.

Researchers develop new method to generate human antibodies

July 24, 2017
An international team of scientists has developed a method to rapidly produce specific human antibodies in the laboratory. The technique, which will be described in a paper to be published July 24 in The Journal of Experimental ...

A sodium surprise: Engineers find unexpected result during cardiac research

July 20, 2017
Irregular heartbeat—or arrhythmia—can have sudden and often fatal consequences. A biomedical engineering team at Washington University in St. Louis examining molecular behavior in cardiac tissue recently made a surprising ...

Want to win at sports? Take a cue from these mighty mice

July 20, 2017
As student athletes hit training fields this summer to gain the competitive edge, a new study shows how the experiences of a tiny mouse can put them on the path to winning.

'Smart' robot technology could give stroke rehab a boost

July 19, 2017
Scientists say they have developed a "smart" robotic harness that might make it easier for people to learn to walk again after a stroke or spinal cord injury.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.