Study Rationale: In people with Parkinson’s disease (PD), chronic inflammation and metabolic reprogramming triggers neuronal cell death. Impaired function of the proteins involved in cellular respiration—the breakdown of food molecules in structures called mitochondria—is associated with an increased production in reactive chemicals that drive neuroinflammation. Itaconate is a small molecule, produced by immune cells, that can transiently regulate mitochondrial metabolic activity by inhibiting a respiratory protein called succinate dehydrogenase (SDH). This inhibition modulates the productive of reactive chemicals and reduces inflammation. In this study, we will explore whether itaconate can dampen neuroinflammation and improve the overall outcome of PD.
Hypothesis: We hypothesize that by transiently modifying mitochondrial metabolism, itaconate can reduce the neuronal injury that is induced by inflammation.
Study Design: We will begin by characterizing the effects of itaconate on metabolism and inflammatory signaling in isolated brain cells. These experiments will allow us to test the hypothesis that itaconate modulates brain cell metabolism and inflammatory signaling. Next, we will elucidate the physiological benefits of itaconate as an adjuvant for improving metabolic homeostasis and limiting neuroinflammation in a preclinical model of PD. These studies will test the hypothesis that itaconate is a metabolic regulator that improves outcomes in neurotoxic models of PD by buffering inflammation and modulating metabolism.
Impact on Diagnosis/Treatment of Parkinson’s disease: If successful, our results will advance the development of new and improved therapeutic strategies to reduce the burden of PD. Ultimately, we aim to adapt itaconate-based treatments to decrease neuronal cell death in PD.
Next Steps for Development: These are the first studies using itaconate to mitigate PD-related cellular injuries. Because itaconate is naturally produced by immune cells, it should prove to be soluble, stable, low cost and tolerable. Itaconate should therefore gain FDA approval and can be available to treat PD in the US and abroad.