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• W2981220278 abstract "Haploinsufficiency in the progranulin gene (GRN) accounts for 10% of familial frontotemporal dementia cases. We have previously shown that the progranulin protein (PGRN) is protective in mouse models of Alzheimer's disease. How haploinsufficiency of the GRN gene causes neurodegeneration in FTD and worsens Alzheimer's disease phenotypes is poorly understood. Deficiency of PGRN leads to alterations in phagocytosis in C. elegans and in vitroprimary microglia derived from mice. MerTK and Axl tyrosine kinases are apoptotic receptors that tether microglia (professional phagocytes) to apoptotic cells, thereby initiating phagocytosis and regulating cell turnover, homeostasis and the inflammatory response to dying cells. We used biochemical and cell reporter systems to assay the interaction between PGRN and MerTK/Axl. We used human microglia induced from iPSC to evaluate in vitro phagocytic capability of GRN-/- vs isogenic GRN+/+ microglia in the presence of exogenous recombinant human PGRN. We generated Mer+/-GRN-/-, Mer+/+GRN-/-, Axl+/-GRN-/- and Axl+/+GRN-/- littermate mice and compared their performance to that of WT mice of the same background on a battery of cognitive and social tests. Histological analysis and RNAseq of mouse brain tissue and RNAseq analysis of human microglia under noninflammatory, inflammatory, and apoptotic conditions were performed. Our data show a novel interaction between PGRN and the apoptotic receptors MerTK and Axl. SPR and cell reporter assays show PGRN directly interacts with MerTK and Axl. Exogenous PGRN inhibits phagocytosis of apoptotic cells by induced human microglia in vitro. Loss of PGRN and haploinsufficiency of MerTK impair cognitive performance in Mer+/-GRN-/- mice and have synergistic effects on TDP-43 mis-localization, a hallmark of PGRN deficient FTD pathology. Finally, loss of PGRN dysregulates inflammatory pathways in induced human microglia in response to inflammatory or apoptotic stimuli. Our data show that PGRN may serve as a modulator of phagocytosis and downstream signaling via direct binding to phagocytic receptors. These data suggest a novel pathway through which PGRN regulates phagocytosis and maintains homeostasis and opens new therapeutic avenues for diseases such as FTD and AD in which PGRN deficiency may be causal or contributory." @default.
• W2981220278 created "2019-10-25" @default.
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• W2981220278 date "2019-07-01" @default.
• W2981220278 modified "2023-09-27" @default.
• W2981220278 title "P4-511: A NOVEL ROLE FOR THE FTD-CAUSING PROTEIN PROGRANULIN IN APOPTOSIS SIGNALING" @default.
• W2981220278 doi "https://doi.org/10.1016/j.jalz.2019.08.057" @default.
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