Controlling Brain Inflammation to Reduce Collateral Damage in Parkinson's Disease
Inflammation is the body’s way of dealing with injury or foreign organisms, such as bacteria or viruses. While effective, the inflammatory process can cause collateral damage to cells and tissues if not managed appropriately. As the body ages, the risk of chronic inflammation — when the inflammatory alarm stays on even when is no threat — increases. Chronic inflammation in the brain has been observed in Parkinson’s disease (PD), and the associated damage likely contributes to the progressive loss of dopamine neurons that characterize the disease. Ray Norton, PhD, recipient of a Parkinson’s Foundation 2023 Bill and Amy Gurley Impact Award, believes that PD-induced inflammation involves brain cells called microglia, and he has a plan for how to inhibit those brain cells to reduce inflammation and potentially slow down disease progression.
In healthy brains, microglia release chemical signals —called cytokines— that turn on the inflammation alarm when facing a threat. This recruits immune cells to deal with the threat, after which the microglia stop releasing inflammation cytokines and the alarm turns off. In PD, microglia can malfunction in ways that make them release those cytokines inappropriately and in greater amounts, triggering inflammatory responses that can damage and ultimately break down sensitive neurons. Prof. Norton, from his lab at Monash University in Melbourne, Australia, has developed a peptide that binds to a specific protein on the microglia, which is over-active in PD, leading to cytokine release and neuron death. The peptide developed by Prof. Norton has the ability to bind to this protein and inhibit (i.e., block) its function, thus preventing the release of those inflammatory cytokines and subsequent neuron damage that occurs in PD.
Prof. Norton, together with his collaborators Joe Nicolazzo and Dorothy Wai at Monash, David Finkelstein at the Florey Institute of Neuroscience and Mental Health and Gyorgy Panyi at the University of Debrecen, will first be looking at how the levels of the microglial protein change in two different mice models of PD, helping them understand how those changes may contribute to increased brain inflammation. Next, he will use neurons in Petri dishes from PD and non-PD donors to assess how well his inhibitor molecule prevents the release of inflammatory cytokines in healthy and disease contexts. This will show if this inhibitor works with human microglia and could be biologically effective in the brains of those with PD. Finally, Prof. Norton will modify the design of his inhibitor molecule to make it better at crossing the body’s blood-brain barrier, a system built to protect the brain from invaders, but which can also block drugs from passing through. All these experiments will help develop this microglia inhibitor into a strong candidate for new PD therapies that reduce brain inflammation to limit and prevent neuron damage from the disease.
Prof. Norton is thrilled to have received this award to continue his work, and is excited about its potential to help those with PD: “Successful completion of this project will underpin the development of a potent and target-specific drug lead with the potential for rapid clinical translation for the treatment of Parkinson’s disease. It would be personally very rewarding to see the peptide inhibitor I developed become a clinical candidate for Parkinson’s disease.”
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