Researchers introduce a groundbreaking approach to combating neurodegenerative diseases

Researchers led by Northwestern University and the University of Wisconsin-Madison have introduced a breakthrough approach aimed at fighting neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS).

In a new study, researchers have discovered a new way to boost the body’s antioxidant response, which is crucial for cellular protection against the oxidative stress involved in many neurodegenerative diseases.

The study was published today (February 16) in the journal Advanced Materials.

Nathan Gianneschi, the Jacob & Rosaline Cohn Professor of Chemistry at Northwestern’s Weinberg College of Arts and Sciences and a member of the International Nanotechnology Institute, led the work with Jeffrey A. Johnson and Delinda A. Johnson of the University of Wisconsin-Madison School of Pharmacy.

Targeting neurodegenerative diseases

Alzheimer’s disease, characterized by the accumulation of beta-amyloid plaques and tau protein tangles. Parkinson’s disease, known for the loss of dopaminergic neurons and the presence of Lewy bodies. and ALS, which involves motor neuron degeneration, all share a common thread of oxidative stress that contributes to disease pathology.

The study focuses on disrupting the Keap1/Nrf2 protein-protein interaction (PPI), which plays a role in the body’s antioxidant response. By preventing the degradation of Nrf2 through selective inhibition of its interaction with Keap1, the research holds promise for mitigating the cellular damage that underlies these debilitating conditions.

“We have targeted Nrf2 as a major target for the treatment of neurodegenerative diseases for the past two decades, but this new approach to activating the pathway holds great promise for the development of disease-modifying therapies,” said Jeffrey Johnson.

Limitations of current therapeutic methods

The research team set out to tackle one of the most challenging aspects of treating neurodegenerative diseases: the precise targeting of PPIs within the cell. Traditional methods, including small molecule inhibitors and peptide-based therapies, have failed due to lack of specificity, stability, and cellular uptake.

The study introduces a novel solution: protein polymers or PLPs are high-density brush macromolecular architectures synthesized via ring-opening metathesis polymerization (ROMP) of norbornenyl-peptide-based monomers. These globular, proteomimetic structures display bioactive peptide side chains that can penetrate cell membranes, exhibit remarkable stability, and resist proteolysis.

This targeted approach to inhibit Keap1/Nrf2 PPI represents a significant leap forward. By preventing Keap1 from marking Nrf2 for degradation, Nrf2 accumulates in the nucleus, activating the Antioxidant Response Element (ARE) and inducing the expression of detoxification and antioxidant genes. This mechanism effectively enhances the cellular antioxidant response, providing a powerful therapeutic strategy against the oxidative stress involved in many neurodegenerative diseases.

The innovation behind protein polymers

PLPs, developed by Gianneschi’s team, could represent a breakthrough in halting or reversing damage, offering hope for improved treatments and outcomes.

By focusing on the challenge of activating processes critical to the body’s antioxidant response, the team’s research offers a new solution. The team provides a powerful, selective method that enables enhanced cellular protection and offers a promising therapeutic strategy for a range of diseases, including neurodegenerative conditions.

Through modern polymer chemistry, we can begin to think about mimicking complex proteins. The promise lies in developing a new method for designing therapeutics. This could be a way to treat diseases such as Alzheimer’s and Parkinson’s, among others, where traditional approaches have struggled.”

Nathan Gianneschi, the Jacob & Rosaline Cohn Professor of Chemistry at Northwestern’s Weinberg College of Arts and Sciences

This approach not only represents a significant advance in targeting transcription factors and disordered proteins, but also demonstrates the versatility and potential of PLP technology to revolutionize the development of therapeutics. The technology’s modularity and efficiency in inhibiting the Keap1/Nrf2 interaction highlight its potential for impact as a therapeutic, but also as a tool to study the biochemistry of these processes.

A partnership of minds

Underscoring the collaborative nature of the study, Gianneschi’s team worked closely with experts in various disciplines, demonstrating the rich possibilities of combining materials science with cell biology to address complex medical challenges.

“We were contacted by Professor Gianneschi and our colleagues who proposed the use of this new PLP technology in neurodegenerative diseases because of our previous work on Nrf2 in models of Alzheimer’s disease, Parkinson’s disease, ALS and Huntington,” Jeffrey Johnson said. “We had never heard of this approach to activating Nrf2 and immediately agreed to start this collaborative effort that led to great data and this publication.”

This collaboration highlights the importance of interdisciplinary research in the development of new therapeutics.

Effect

By developing this innovative technology, Gianneschi, his colleagues at the International Institute for Nanotechnology and the Johnson Laboratory at the University of Wisconsin-Madison are not just advancing the field of medicinal chemistry, but are breaking new ground in combating some of the most challenging and devastating neurodegenerative diseases facing society today. As this research moves toward clinical application, it may soon offer new hope to those suffering from oxidative stress diseases such as Alzheimer’s and Parkinson’s.

“By controlling materials at the scale of single nanometers, we are opening up new possibilities in the fight against diseases that are more widespread than ever, but remain incurable,” said Gianneschi. “This study is just the beginning. We are excited about the possibilities as we continue to explore and expand the development of macromolecular drugs capable of mimicking certain aspects of proteins using our PLP platform.”