Sex-specific microglial responses to glucocerebrosidase inhibition: relevance to GBA1-linked Parkinson disease

Microglia are heterogenous cells characterized by distinct populations each contributing to specific biological processes in the nervous system, including neuroprotection. To elucidate the impact of sex-specific microglia heterogenicity to the susceptibility of neuronal stress, we analysed the dynamic changes in shape and motility occurring in primary mouse microglia following pro-inflammatory or neurotoxic insults, thus finding sex-specific responses of microglial subpopulations. Male microglia exhibited a pro-inflammatory phenotype, whereas female microglia showed enhanced neuroprotective capabilities associated with the activation of Nrf2 detoxification pathway in neurons. The sex difference in neuroprotective functions is lost by inhibition of glucocerebrosidase, the product of the GBA1 gene, mutations of which are the major risk factor for Parkinson’s disease (PD). This finding is consistent with the increased risk of PD observed in female carriers of GBA1 mutation, when compared with wild type population, suggesting a role for microglial functionality in the etiopathogenesis of PD-GBA1.