A recently published study from 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 related disorders.
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 disease. Although there are medications that control the motor symptoms of the disease, there are no effective treatments for the cognitive symptoms.
When patients are diagnosed with Parkinson’s disease, 25% to 30% already have mild cognitive impairment. As the disorder progresses, 50% to 70% of patients complain of cognitive problems. The sad thing is that we don’t have a clear way to treat cognitive decline or dementia in Parkinson’s disease.”
Lalitha Madhavan, MD, PhD, associate professor of neurology, University of Arizona College of Medicine – Tucson
A research team led by Madhavan, in collaboration with Torsten Falk, PhD, a research professor of neurology, is investigating PNA5, which was developed by Meredith Hay, PhD, a professor of physiology. They recently published an article in Experimental neurology showing that PNA5 appears to have a protective effect on brain cells in an animal model.
“With PNA5, we target cognitive symptoms, but above all we try to prevent further degeneration from occurring,” says Kelsey Bernard, PhD, a postdoctoral researcher in the Madhavan Lab and first author of the study. “By following the protective route, we can hopefully prevent cognitive decline from continuing.”
Reversing inflammation
The causes of neurodegenerative diseases are largely mysterious, but current thinking is that they involve inflammation, a normal function of the immune system that is usually short-lived in response to infections or wounds. However, if the inflammation becomes chronic, it can cause permanent damage.
Bernard said inflammation plays an important role in Parkinson’s disease when microglia, specific immune cells in the brain, enter a supercharged state.
“Normally, microglia are looking for things like viruses or injuries and secrete substances that block the damage,” she said. “In Parkinson’s disease, when microglia are continuously activated, they can cause further damage to surrounding tissue. That’s what we see in Parkinson’s brain, especially in regions associated with cognitive decline.”
The team found that these supercharged microglia flooded their environment with an inflammatory chemical, supporting previous research linking that chemical to cognitive status.
“This inflammatory substance can interact directly with neurons in a part of the brain that is important for learning and memory,” Bernard said.
After treatment with PNA5, researchers saw blood levels of the inflammatory chemical decrease, which correlated with reduced brain cell loss. They said they believe PNA5 reverses the microglia’s overactive immune response and brings them closer to a normal state.
The researchers hope that by suppressing the production of this inflammatory substance, PNA5 can protect the brain.
Expansion of treatment options
In developing PNA5, Hay, working with Robin Polt, PhD, professor of chemistry and biochemistry in the U of A’s College of Science, made small adjustments to the structure of a chemical that the body naturally makes, improving its ability to enter the brain is increased. and stay there longer. Hay is studying the potential of PNA5 in the treatment of other forms of dementia, such as vascular dementia and Alzheimer’s disease.
“It has already been tried and tested in other models, and that makes me more optimistic,” says Madhavan, who is a member of the BIO5 Institute along with Polt and Hay.
She said she hopes the team’s research on 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 see it as a cog in the wheel: there will be other medications that support other aspects of Parkinson’s disease. Taking multiple medications is never fun, but it is a complex condition and there can only be complex solutions,” said them. . “The beauty of the brain is its interconnectedness, but it also contributes to its complexity.”
The researchers said their next steps include conducting further research to identify biomarkers, refine dosages, investigate sex differences and figure out how PNA5 might work.
“PNA5 appears to have the ability 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 result of Bernard’s PhD research, which she 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 correctly and what makes them go wrong.”
This research was supported in part by the Michael J. Fox Foundation under award no. MJFF 024922, the National Institutes of Health under award no. T32 AG1081797 and the ARCS Foundation Scholarship.
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Magazine reference:
Bernard, K., et al. (2024). The angiotensin (1–7) glycopeptide PNA5 improves cognition in the achronic progressive mouse model of Parkinson’s disease through modulation of neuroinflammation. Experimental neurology. doi.org/10.1016/j.expneurol.2024.114926.