Protein-like polymer may limit oxidative stress, protect nerve cells

Early research finds way to activate protein known for antioxidant effects

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by Andrea Lobo |

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An illustration of the brain and its nerve cells.

A newly developed molecule showed an ability in lab studies to activate antioxidant responses in brain cells by altering how two proteins, believed to be involved in the development of Parkinson’s disease and other neurodegenerative conditions, interact.

The small molecule, known as a protein-like polymer, is designed to bind to target proteins as if it were a protein. Specifically, this protein-like polymer works to block the interaction between Nrf2 and Keap1, proteins involved in the cellular response to oxidative stress — a type of cell damage — within cells of the brain.

And it showed a potential to do so without the unwanted effects that have hampered previous work into small molecules targeting the Keap1/Nrf2 pathway, scientists report.

“It’s hard to get drugs into the brain, but it’s also been very hard to find drugs that activate Nrf2 without a lot of off-target effects,” Jeffrey Johnson, PhD, a professor at the University of Wisconsin-Madison School of Pharmacy, said in a university news release.

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Findings are described in the article, “Inhibiting the Keap1/Nrf2 Protein-Protein Interaction with Protein-Like Polymers,” published in Advanced Materials.

Nrf2 is a transcription factor, a specific type of protein that turns genes on and off within cells, that plays an important role in fighting oxidative stress in cells. Keap1 binds to Nrf2 to control its activation. Under normal conditions, the two proteins are bound together; under conditions of cellular stress, Keap1 releases Nrf2 to enhance its antioxidant role.

Previous research has suggested that increasing Nrf2’s activity, particularly in brain cells, could be a way of treating neurodegenerative diseases such as Alzheimer’s.

But work into “indirect small molecule Keap1/Nrf2 inhibitors” had a “relatively low specificity for the large Keap1 protein target and as a result, they exhibit off-target effects that are largely not understood,” the researchers wrote.

This study resulted from a collaboration between a team led by Johnson and another led by Nathan Gianneschi, a chemistry professor at Northwestern University and member of its International Institute for Nanotechnology. Gianneschi’s team developed the polymer, which after further refinement, Johnson’s team tested in cells models and brain cells from mice.

“We don’t have the expertise in biomaterials,” said Delinda Johnson, PhD, a senior scientist at the University of Wisconsin-Madison school and study author. “So getting that from Northwestern and then moving forward on the biological side here” was a goal.

Both teams were connected by Robert Pacifici, chief science officer at the CHDI Foundation, which funds research in Huntington’s disease, another neurodegenerative condition. The foundation has funded work led Jeffrey Johnson and Gianneschi in the past.

Polymer worked to enhance antioxidant response within cells in lab

Results in several cell models showed that the new polymer effectively bound to Keap1, which released Nrf2 to accumulate in the cell’s nucleus, where it could activate the antioxidant response element (ARE). ARE is a sequence of DNA found in specific parts of certain genes that activates genes involved in the antioxidant response within cells.

Next, the researchers evaluated if the polymer’s action increased ARE activation in nerve cells derived from mouse models, kept in the lab under controlled conditions. These cells included both neurons and astrocytes — star-shaped cells of the brain that play a supportive role for neurons and are involved in degenerative disease mechanisms.

Findings again supported the polymer’s ability to block the Keap1/Nrf2 pathway and without unwanted, off-target effects.

A significantly higher effect was seen in astrocytes compared with neurons.

“This is supported by the important role of … astrocytes in neurodegenerative [mechanisms] …  and demonstrates that while the PLPs [protein-like polymers] penetrate cells, they have a preferential therapeutic effect in the physiologically relevant cell types,” the researchers wrote.

“Keap1/Nrf2-inhibitory PLPs have the potential to impact the treatment of disease states associated with dysregulation of oxidative stress, such as [neurodegenerative diseases],” they added.

Researchers now are moving into studies in mouse models of neurodegenerative diseases, focusing “on assessing ARE activation, [pharmacological] properties, biodistribution, and toxicity of the Keap1/Nrf2-inhibiting PLPs” in living animals.