Dysregulated microglial Ca2+ homeostasis as a pathogenic contributor and therapeutic target in Friedreich’s ataxia

The brain cell type-specific contribution to neurodegeneration in FA is not well understood. Neurons are known to be susceptible to loss of frataxin, however whether microglia, the resident immune cells of the brain, exacerbate and/or also have a primary contribution to the pathogenesis is still under investigation. With this grant, Dr Pernaci will use FA stem cells to differentiate microglia and neurons. She will investigate how FXN deficiency impacts microglia activity and whether diseased microglia influence neuronal physiology and exacerbate neurodegeneration and if so, by what mechanism. Previous studies have identified altered microglial Ca2+ oscillations as impacting healthy neuronal physiology. Ca2+ is an important signaling molecule that regulates many activities in the cell and needs to be finely regulated. Microglia heavily rely on intracellular Ca2+ waves. Dr Pernaci hypothesizes that loss of FXN protein in microglia impacts structural and functional communication between mitochondria and other cellular compartments important for maintaining Ca2+ homeostasis. These alterations result in impaired Ca2+ exchange between cellular compartments, thereby triggering a cellular stress response leading to neuroinflammation and ultimately contributing to FA pathology. Dr Pernaci will target the restoration of Ca2+ transients in FA microglia as a novel therapeutic target and determine whether restoring Ca2+ homeostasis attenuates the FA microglial disease phenotype and alleviates the microglia-mediated impairments.