How does FA impact the brain's immune system?

This project aims to use induced pluripotent stem cells to investigate the mechanisms causing malfunction and death of vulnerable cells in the nervous system in FA and to study the potential toxic or protective effect of microglia – cells that remove cellular debris and foreign invaders from the brain and spinal cord- on frataxin-deficient neurons. This project will use an induced pluripotent stem cell (iPSC)-based neuronal model for Friedreich ataxia (FA) to investigate the mechanisms causing malfunction and death of vulnerable cells in the nervous system, with implications for therapies. iPSCs are derived from skin or blood cells and “reprogrammed” to become undifferentiated cells that resemble those in the embryo. iPSCs can be differentiated into different cell types by using appropriate techniques. The Pandolfo laboratory has experience in turning FA iPSCs into neurons, and the Stifani lab has set up methods to turn them into microglia, other cells found in the nervous system. Microglial cells are not neurons; they are related to a type of white blood cells (macrophages) and “keep the brain clean” by removing cellular debris. Microglia may be protective for the brain but can also be deleterious by promoting inflammation. This proposal aims to characterize microglia obtained from FA iPSCs and compare them with those obtained from healthy control iPSCs. Dr. Pandolfo and Dr. Stifani hypothesize that microglial cells in FA will show a signature of inflammation that would point to their involvement in the disease pathology. They will assess the functional properties of FA microglia and explore if its interaction with neurons promotes neurodegeneration or is protective. For this purpose, they will investigate how FA and control microglia interact with FA and control neurons. These findings will define a role of this cell type and of inflammation in FA, indicating potential therapeutic targets.