Investigating microglial phenotypes and functions in the pathogenesis of Friedreich’s ataxia

The contribution of cells other than neurons to the pathogenesis of FA has been poorly investigated. This proposal seeks to shed light into how low frataxin affects the immune cells of the central nervous system, i.e. the microglia. Microglia are emerging as key players in different aspects of brain function, including neuron-to-neuron contact (synapse) remodeling, a critical step in assembling neuronal circuits. While it has been previously demonstrated that pro-inflammatory microglia populate affected brain areas of FA patients, Dr D’Ambrosi and her collaborators recently showed that cerebellar microglia from an FA mouse model of the disease display altered features and show decreased levels of key markers involved in synapse shaping during neurodevelopment. These results suggest an impairment of microglia functions during the early stages of the disease that can potentially contribute to the overt neuropathology characterizing FA in later stages of the disease. With this grant, Dr D’Ambrosi will analyze the role of microglia in the early stages of cerebellar development in FA mice and determine how microglia obtained from stem cells derived by FA patients affects neuron activity, especially in the context of synaptic regulation. The identification of impaired mechanisms affected by microglia could help develop future therapeutic strategies that target FA early pathogenic events.