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• W2461589796 abstract "Progranulin (GRN) is a ubiquitously expressed, cysteine-rich, secreted glycoprotein. Mutations in the GRN gene have been identified as a cause of frontotemporal dementia (FTD) seen pathologically as a form of frontotemporal lobar degeneration (FTLD). It is suggested that non-loss-of-function GRN mutations cause FTD. Another protein, TAR DNA-binding protein of about 43 kDa (TDP-43) constitutes a significant portion of the ubiquitinated protein aggregate in tau-negative FTLD (FTLD-U). TDP-43 is found to be abnormally phosphorylated, mislocalized to the cytoplasm from the nucleus, and cleaved to produce aggregation prone C-terminal fragments (CTFs) in GRN-associated FTD. Currently, only mislocalization of TDP-43 to the cytoplasm is observed experimentally in neuronal cells upon persistent GRN knockdown. Evidently, the interaction of GRN mutations and its downstream effect on TDP-43 is unclear. Here, we hypothesize that the GRN mutations result in an abnormal TDP-43 processing thus causing a toxic gain of function in cells. To examine the effect of GRN mutations on TDP-43 modifications, the HEK293T and microglial (H4) cell lines was transfected with GRN-WT plasmids and FTD related mutations and evaluated by Western blot, viability, cellular fractionation, confocal microscopy, and immunoprecipatation. GRN mutations caused TDP-43 to be redistributed to the cytoplasm and aberrantly cleaved. There are no significant differences in TDP-43 protein levels in cells that overexpress WT GRN versus GRN missense mutations. These results are confirmed in GRN knockdown cells. However, in the missense C521Y mutation, there is significant increase in TDP-43 protein levels. Our studies confirm that GRN mutations in FTLD-U confer neurotoxicity through TDP-43 processing. Increased TDP-43 protein levels when the C521Y mutant is overexpressed suggest either a direct interaction of the PGRN protein with TDP-43 or an inhibition in the protein degradation pathway. This link provides a promising lead into further experiments to investigate the toxic downstream effect of PGRN mutations through TDP-43 interaction." @default.
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• W2461589796 date "2015-07-01" @default.
• W2461589796 modified "2023-10-16" @default.
• W2461589796 title "P2‐039: Progranulin missense mutations causing frontotemporal lobar degeneration misregulate endogenous TDP‐43" @default.
• W2461589796 doi "https://doi.org/10.1016/j.jalz.2015.06.575" @default.
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