Scientists at Oregon State University have discovered a new class of therapeutic targets for people with neurodegenerative diseases like Alzheimer’s, Parkinson’s, and Lou Gehrig’s disease.
Oxidized proteins are one of the potential targets, and researchers at the Ohio State University College of Science are working to find the best technique to attack them. A pharmacological target is any molecule that is essential to the disease process, meaning that disrupting it can prevent or delay disease progression.
Findings were published in Redox Biology.
Nerve cells lose function over time and eventually die, resulting in neurodegenerative disorders. According to the National Institutes of Health, the diseases impact millions of individuals worldwide, with Alzheimer’s and Parkinson’s being the most frequent.
According to the Alzheimer’s Disease Association, over 6 million Americans have Alzheimer’s disease, and another 1 million have Parkinson’s disease, according to the Parkinson’s Foundation.
By understanding the ways that oxidation modifies the Hsp90 structure, and how the oxidized protein works in the cells, we can look for drugs that bind to the modified structure of Hsp90 and stop its toxic function without affecting the activity of normal Hsp90 in healthy tissues. That means such drugs should have minimal to no side effects.
Maria Clara Franco
The risk of acquiring a neurological condition grows with age, which implies that as people live longer, the number of cases will likely increase in the future decades, according to the NIH.
According to Franco, an assistant professor of biochemistry and biophysics, diseased cells create peroxynitrite, the most powerful oxidant a cell can produce, in medical illnesses requiring inflammation, such as neurogenerative disorders.
An oxidant, also known as an oxidizing agent or oxidizer, is a substance that may oxidize (remove electrons from) other compounds in chemical reactions.
Inflammation causes oxidative stress, which causes the creation of oxidants and free radicals, which can damage biological components including DNA, lipids, and proteins, as well as create a variety of health problems.
When peroxynitrite oxidizes Hsp90, or heat shock protein 90, it activates signals inside the cells that cause them to die by “suicide” in a process called apoptosis, according to Franco and researchers at Oregon State, the University of Central Florida, and Rollins College.
“We had earlier found that oxidation of specific molecules by peroxynitrite leads to the death of motor neurons, the cells that carry signals from the brain to the muscles to coordinate muscle movement,” said OSU’s Maria Clara Franco. “Now we know that the oxidation of different parts of Hsp90 can elicit different toxic functions in the protein.”
Hsp90’s typical job is to maintain healthy cellular activities, however oxidation can affect the three-dimensional structure of a protein like Hsp90, causing it to lose its function, according to Franco.
“By understanding the ways that oxidation modifies the Hsp90 structure, and how the oxidized protein works in the cells, we can look for drugs that bind to the modified structure of Hsp90 and stop its toxic function without affecting the activity of normal Hsp90 in healthy tissues,” she said. “That means such drugs should have minimal to no side effects.”
Oregon State undergraduate student Asra Noor helped Franco lead the study along with Megan Jandy and Pascal Nelson, researchers at the University of Central Florida. Collaborators also included Carrie Marean-Reardon, Ryan Mehl and Alvaro Estevez of OSU. The National Institutes of Health supported this research.
