UCSF

Loss-of-function mutations in progranulin (GRN) that result in haploinsufficiency of the progranulin protein (PGRN) have been causally linked to frontotemporal dementia (FTD). PGRN levels are tightly regulated, as high levels cause cancer and low levels cause FTD. PGRN is a secreted glycoprotein implicated in cell survival, proliferation, and inflammation. In the central nervous system (CNS), PGRN is expressed by neurons and microglia, but its cellular functions remain unclear. We generated a murine model of PGRN-deficiency in order to begin to elucidate the CNS function of PGRN, and to model aspects of human FTD. We explored the cell type contributions of PGRN deficiency to CNS injury using the acute toxin model of 1-methyl-4-(2'methylphenyl)-1,2,3,6-tetrahydrophine (MPTP), which is known to cause both neuroinflammation and neuron death. We determined that PGRN deficiency leads to uncontrolled neuroinflammation that is detrimental to neuron survival. Therefore, microglial PGRN is critical for regulating neuroinflammation following acute brain injury. The PGRN deficient mice were aged in order to determine whether they model FTD behaviorally and/or pathologically. The homozygous PGRN deficient mice developed behavioral changes that may be linked to their age-dependent CNS inflammatory phenotype. These data suggest the importance of microglial PGRN in normal aging. Interestingly, the heterozygous and homozygous PGRN deficient mice have similar early behavioral changes, but the heterozygous mice lack any gross neuroinflammatory pathology. These early behavioral phenotypes in PGRN-deficient animals are linked to alterations in neuronal activity, suggesting that PGRN is important for neuronal function. It is likely that PGRN deficiency causes early neuron dysfunction that triggers gliosis. The gliosis then proceeds uncontrolled due to the lack of microglial PGRN that exacerbates the neuronal phenotype, thereby causing a vicious positive feedback loop that is detrimental to neuronal function and survival. Our data suggests that PGRN is important for both neuronal and microglial function in normal aging. Further characterization of these aging phenotypes in cell-type specific models of PGRN deficiency are critical for exploring this hypothesis. Overall, the development of therapeutic strategies to regulate PGRN levels in both neurons and microglia has implications for both neurodegeneration and CNS injury.