Parkinson's disease (PD) has the second highest rate of occurrence among all neurological diseases, and this is expected to increase sharply with an aging population. One of the underlying causes of PD progression is ongoing and persistent inflammation, which starts early in the disease, and increases as the PD progresses after diagnosis. Remarkably, inflammation is present in all animal models of PD, irrespective of the different initiating causes of PD in these models, suggesting that it is a common underlying feature of PD that occurs no matter what the specific triggers or causes could be in different individuals. This uncontrolled inflammation, over a prolonged period, has been shown to damage the vulnerable dopamine-producing neurons that are progressively lost in people with PD. For this reason, limiting or stopping the underlying inflammatory processes and mechanisms in PD is considered one of the most promising approaches by which to slow or stop the progression of the disease. While the precise causes of inflammation in PD are still being studied, emerging evidence points to several causes, including neurotoxic chemical and environmental exposures, microbial dysbiosis of the gut, and misfolded synuclein aggregates that accumulate in PD. Under normal circumstances, the body has natural protective mechanisms, which function like brakes to limit and resolve harmful inflammation, preventing it from spiralling out of control and causing damage to vulnerable cells and tissues in the brain and gut. Emerging evidence suggests that these protective mechanisms, which keep inflammation in check, are somehow lost or dysregulated in PD, presumably at the early stages of the disease. However, to date, the protective pathways and mechanisms that function as brakes to limit inflammation in PD remain unknown.

Based on our exciting preliminary results in PD patient samples, animal models, and cell culture studies, we believe we have discovered the first innate protective pathway that functions to limit and resolve inflammation in PD. This pathway, called NLRX1, normally functions as a powerful brake on inflammation in healthy individuals. Remarkably, we found that NLRX1 levels are profoundly lost or reduced in PD patients, both in the blood and in the brain. This suggests that in PD, the loss of NLRX1 could be the cause of unresolving and persistent inflammation, as the braking system that normally keeps inflammation in check is lost or not functional, thereby allowing inflammation to spiral out of control. Crucially, our studies so far suggest that this protective NLRX1 pathway could be re-activated using small molecules to suppress inflammation and promote the survival of dopaminergic neurons that are lost in PD patients. Our proposed studies in this project will systematically confirm the role of NLRX1 as a key player in suppressing and resolving inflammation.

For these studies in Aim 1 and Aim 2, we will use samples from human PD patients and healthy controls, as well as several animal models that are relevant to neurotoxicant chemical exposures linked to PD. We will also test if animals lacking the protective NLRX1 braking system progress faster in experimental models of PD, confirming our theory on the role of NLRX1 in PD. Most importantly, in Aim 3, we will develop a new series of NLRX1-activating molecules as new treatments for PD that will be capable of crossing the blood brain barrier to suppress inflammation in the brain and systemically. We believe these compounds will resolve uncontrolled inflammation in PD and promote the survival of dopaminergic neurons which would slow or stop PD progression. Further, our data suggests that loss of protective NLRX1 occurs no matter which initiating trigger or mechanism is used to cause PD in disease models. This suggests that activation of NLRX1 would be effective no matter what the potential underlying cause of PD could be. Therefore, we anticipate that our NLRX1-activating drugs could have immense potential to slow or stop the progression of PD by attacking and resolving the underlying root cause of uncontrolled inflammation that leads to the loss of dopaminergic neurons.