GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function. Here, we found that Grn-/- mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitive enhancer of lysosomal proteolysis and lipolysis. Grn-/- brains also showed an age-dependent, secondary storage of glucocerebrosidase substrate glucosylsphingosine. We investigated a protein replacement strategy by engineering protein transport vehicle (PTV):PGRN-a recombinant protein linking PGRN to a modified Fc domain that binds human transferrin receptor for enhanced CNS biodistribution. PTV:PGRN rescued various Grn-/- phenotypes in primary murine macrophages and human iPSC-derived microglia, including oxidative stress, lysosomal dysfunction, and endomembrane damage. Peripherally delivered PTV:PGRN corrected levels of BMP, glucosylsphingosine, and disease pathology in Grn-/- CNS, including microgliosis, lipofuscinosis, and neuronal damage. PTV:PGRN thus represents a potential biotherapeutic for GRN-FTD.
Biological Products/therapeutic use , Brain/metabolism , Lysosomal Storage Diseases/therapy , Progranulins/therapeutic use , Animals , Bone Morphogenetic Proteins/metabolism , Endosomes/metabolism , Female , Frontotemporal Dementia/blood , Frontotemporal Dementia/cerebrospinal fluid , Gliosis/complications , Gliosis/pathology , Humans , Induced Pluripotent Stem Cells/metabolism , Inflammation/pathology , Lipid Metabolism , Lipofuscin/metabolism , Lysosomes/metabolism , Macrophages/metabolism , Male , Membrane Glycoproteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microglia/metabolism , Nerve Degeneration/pathology , Phenotype , Progranulins/deficiency , Progranulins/metabolism , Receptors, Immunologic/metabolism , Receptors, Transferrin/metabolism , Tissue Distribution
