Study Rationale: Inflammation is recognized as a factor in the progression of Parkinson’s disease (PD). The PD-associated genes PINK1 and Parkin are involved in eliminating damaged cell components such as mitochondria. Mutations in PINK1 and Parkin impair this quality control, which leads to the leakage of mitochondrial contents—a signal that triggers inflammation via the STING pathway. In this study, we use induced pluripotent stem cells (iPSC) to generate the main cell types found in the brain. We will then identify which cells release mitochondrial contents when stressed, which cells activate STING, and how this inflammatory response spreads within and between cells.
Hypothesis: Using cells derived from iPSC, we will develop a platform for testing drugs that dampen STING signaling. Such drugs have the potential to reduce inflammation in PD.
Study Design: We will collect iPSC from healthy volunteers and from individuals with PD who harbor PINK1 mutations. Additionally, we will use gene-editing tools to generate iPSC in which PINK1 or STING have been knocked out. We will use these collected and engineered iPSC to produce the nerve cells affected in PD, as well as brain immune cells (microglia) and supporting cells (astrocytes). We will then stress these cells, identify and transfer leaked mitochondrial material between cell types and measure the activation of the STING pathway. We will use this information to develop the most relevant model for testing STING pathway inhibitors.
Impact on Diagnosis/Treatment of Parkinson’s disease: This project enhance our understanding of the brain inflammation associated with PD and the role played by the STING pathway. It will also facilitate the development of a PD-relevant cell platform for use in drug testing.
Next Steps for Development: If successful, iPSC from people with a wide range of backgrounds can be used to test drugs that target the STING pathway; such testing will reveal whether STING inhibitors can be used to treat PD broadly or whether particular subsets of patients will benefit from this type of drug.