Enhanced legumain activity links progranulin deficiency to TDP-43 pathology in frontotemporal lobar degeneration
Sophie Robinson,
Marvin Reich,
Maria-Teresa Mühlhofer
et al.
Abstract:Loss-of-function mutations in GRN are 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 in Grn knockout (ko) mice, in human induced pluripotent… Show more
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