Enhanced legumain activity links progranulin deficiency to TDP-43 pathology in frontotemporal lobar degeneration
Robinson, S.; Reich, M.; Muehlhofer, M.-T.; Buschmann, K.; Wauters, E.; Muehlhofer, Q.; Werner, G.; Ahles, A.; Engelhardt, S.; Krenner, C.; Bartels, B.; Gutbier, S.; Reifschneider, A.; Riemenschneider, H.; Reinheckel, T.; Edbauer, D.; Simon, M. J.; Kariolis, M. S.; Logan, T.; Di Paolo, G.; Van Broeckhoven, C.; Damme, M.; Paquet, D.; Haass, C.; Capell, A.
Show 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 stem cell-derived GRN ko microglia, and in FTLD-GRN patients 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-GRN and suggest LGMN as a therapeutic target.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- S-Nitrosylation of CRTC1 in Alzheimer's disease impairs CREB-dependent gene expression induced by neuronal activity 98%
- Amyloid Beta Glycation Induces Neuronal Mitochondrial Dysfunction and Alzheimers Pathogenesis via VDAC1-Dependent mtDNA Efflux 97%
- LRRK2 Suppresses Lysosome Degradative Activity in Macrophages and Microglia Through MiT-TFE Transcription Factor Inhibition 96%
Similar papers in this journal
- Neurons burdened by DNA double strand breaks incite microglia activation through antiviral-like signaling in neurodegeneration. 97%
- Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis 96%
- C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility 96%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.