A recently published study by researchers at the University of Arizona Health Sciences found that a small protein called PNA5 appears to have a protective effect on brain cells, which could lead to treatments for the cognitive symptoms of Parkinson’s disease and disorders. related.
Parkinson’s disease, a neurological disorder best known for causing tremors, stiffness, slow movements, and poor balance, also causes cognitive symptoms that can progress to Parkinson’s dementia. Although there are medications that control the motor symptoms of the disease, there are no effective treatments for its cognitive symptoms.
“When patients are diagnosed with Parkinson’s disease, between 25% and 30% already have mild cognitive impairment. As the disorder progresses to its later stages, between 50% and 70% of patients complain of cognitive problems,” said Lalitha Madhavan, MD, PhD. associate professor of neurology, University of Arizona College of Medicine, Tucson. “The sad thing is that we don’t have a clear way to treat cognitive decline or dementia in Parkinson’s disease.”
A research team led by Madhavan, in collaboration with Torsten Falk, PhD, research professor of neurology, is investigating PNA5, which was developed by Meredith Hay, PhD, professor of physiology. They recently published an article in Experimental neurology demonstrating that, in an animal model, PNA5 appears to have a protective effect on brain cells.
“With PNA5, we’re targeting cognitive symptoms but, in particular, we’re trying to prevent further degeneration from occurring,” said Kelsey Bernard, PhD, a postdoctoral researcher in the Madhavan Laboratory and first author of the study. “By following the protective route, we can hopefully prevent cognitive decline from continuing.”
Reduce inflammation
The causes of neurodegenerative diseases are largely mysterious, but the current thinking is that they involve inflammation, a normal function of the immune system that is usually short-lived in response to infection or injury. However, if the inflammation becomes chronic, it can cause lasting damage.
Bernard said inflammation plays an important role in Parkinson’s disease when microglia, specific immune cells in the brain, go into a supercharged state.
“Normally, microglia look for things like viruses or injuries and secrete substances that block the damage,” he said. “In Parkinson’s disease, when constantly activated, microglia can spread more damage to surrounding tissue. That’s what we see in Parkinson’s brains, particularly in regions associated with cognitive decline.”
The team found that these overloaded microglia flooded their environments with an inflammatory chemical, supporting previous research linking that chemical to cognitive state.
“This inflammatory chemical may interact directly with neurons in a brain region important for learning and memory,” Bernard said.
After treatment with PNA5, the researchers observed that blood levels of the inflammatory chemical decreased, which correlated with reduced brain cell loss. They said they believe that PNA5 reduces the overactive immune response of microglia and brings them closer to a normal state.
Researchers hope that by suppressing the production of this inflammatory chemical, PNA5 can protect the brain.
Expanding treatment options
In developing PNA5, Hay, in collaboration with Robin Polt, PhD, professor of chemistry and biochemistry in the U of A College of Science, made small adjustments to the structure of a chemical the body produces naturally, improving its ability to enter the brain. and stay there longer. Hay is studying the potential of PNA5 in treating other types of dementia, such as vascular dementia and Alzheimer’s disease.
“It’s already been tested in other models, and that makes me more optimistic,” said Madhavan, who, along with Polt and Hay, is a member of the BIO5 Institute.
He said he hopes the team’s research into PNA5 will eventually lead to a drug that people with Parkinson’s disease can take to relieve cognitive symptoms, although they may still need to take other medications to control motor symptoms.
“I think of it as a cog in the wheel: There will be other medications that support other aspects of Parkinson’s. Taking multiple medications is never fun, but it is a complex condition and there can only be complex solutions,” he said. . “The beauty of the brain is the interconnectedness, but it also increases complexity.”
The researchers said their next steps are to conduct more studies to identify biomarkers, refine doses, investigate sex differences and discover how PNA5 might work.
“PNA5 appears to have the potential to stop or slow the progression of Parkinson’s to some extent and could improve the health of brain cells or prevent cells from dying,” Madhavan said.
The publication was the product of Bernard’s doctoral research, which he conducted under the mentorship of co-senior authors Madhavan and Falk.
“The brain is the most interesting part of the body,” Bernard said. “These cells are fascinating: what makes them work properly and what makes them work poorly.”
This research was funded in part by the Michael J. Fox Foundation under award no. MJFF 024922, National Institutes of Health under award no. T32 AG1081797 and the ARCS Foundation Scholarship.