Combatting oxidative stress in neurodegenerative diseases
Oxidative stress is implicated in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Now, researchers have found a way to enhance the body’s protective antioxidant response.
A collaborative effort led by researchers at Northwestern University (IL, USA) and the University of Wisconsin-Madison (WI, USA) has shown that a specific protein–protein interaction involved in regulating the antioxidant response could be a viable therapeutic target for reducing oxidative stress associated with neurodegenerative diseases.
Oxidative stress plays a significant role in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS). By enhancing the body’s antioxidant response, the team is hopeful that they will be able to mitigate the cellular damage inflicted by oxidative stress.
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To achieve this, the team wanted to disrupt the interaction between Nrf2 – a transcription factor that regulates redox homeostasis – and Keap1 – a protein that regulates Nrf2. In non-stressful conditions, Nrf2 and Keap1 are bound in the cytoplasm, signaling that Nrf2 can be degraded. However, in stressful conditions, Nrf2 is unbound from Keap1 and allowed to accumulate in the nucleus, activating the antioxidant response element, which in turn drives the expression of other antioxidant genes.
“We established Nrf2 as a principal target for the treatment of neurodegenerative diseases over the past two decades, but this novel approach for activating the pathway holds great promise to develop disease-modifying therapies,” commented co-author Jeffrey Johnson (University of Wisconsin-Madison).
But the question is, how do we disrupt this protein–protein interaction? Previous research has demonstrated that small molecule inhibitors and peptide-based therapies lack specificity, stability and uptake. Therefore, the current team developed protein-like polymers (PLPs); these high-density brush macromolecular architectures are synthesized using the ring-opening metathesis polymerization (ROMP) of norbornenyl-peptide-based monomers. Their globular, proteomimetic bodies have bioactive peptide side chains, which can pierce cellular membrane.
Using PLPs, the team was able to selectively inhibit the Nrf2/Keap1 interaction, allowing Nrf2 to enhance expression of antioxidant genes and combat the oxidative stress implicated in neurodegenerative disease.
PLPs resist proteolysis and appear to be stable therapeutic material. They offer a robust, selective method for targeting disordered proteins and transcription factors and, thanks to their efficacy in this study, could be key for developing therapeutics in future.
“By controlling materials at the scale of single nanometers, we’re opening new possibilities in the fight against diseases that are more prevalent than ever, yet remain untreatable,” co-author Nathan Gianneschi concluded. “This study is just the beginning. We’re excited about the possibilities as we continue to explore and expand the development of macromolecular drugs, capable of mimicking some of the aspects of proteins using our PLP platform.”