Enhanced legumain activity links progranulin deficiency to TDP-43 pathology in frontotemporal lobar degeneration

Abstract

Loss-of-function mutations inGRNare a major cause of frontotemporal lobar degeneration (FTLD) with TDP-43-positive inclusions. Progranulin (PGRN) loss leads to lysosomal dysfunction, microglial hyperactivation, and TDP-43 deposition, yet the underlying pathomechanism remains unknown. We demonstrate that PGRN slows the maturation and limits the proteolytic activity of the lysosomal protease legumain (LGMN). Accordingly, LGMN activity is strongly elevated inGrnknockout (ko) mice, in human induced pluripotent stem cell-derivedGRNko microglia, and in FTLD-GRNpatients’ brain. Secreted microglial LGMN is internalized by neurons, where it mediates pathological processing of TDP-43, which is prevented by selective LGMN inhibition. In contrast, AAV-mediated overexpression of LGMN in mouse brains promotes TDP-43 processing, the aggregation of phosphorylated TDP-43 and increases plasma neurofilament light chain (NfL), a marker for neuronal loss. Our findings identify LGMN as a link between PGRN haploinsufficiency and TDP-43 pathology in FTLD-GRNand suggest LGMN as a therapeutic target.