The decrease in lysosomal degradation and cathepsin activity in female Grn -/- macrophages and increase in lysosomal acidity in GRN-FTD PBMCs observed herein upon Gpnmb knock-down supports a model in which the reported Gpnmb upregulation in PGRN-deficient mice [18–20] is a compensatory response to protect the lysosome in the absence of PGRN. This evidence concerns the gene CTSS and frontotemporal dementia.