Search

Loss-of-function mutations in progranulin ( GRN) are associated with frontotemporal lobar degeneration with intraneuronal ubiquitinated protein accumulations composed primarily of hyperphosphorylated TDP-43 (FTLD-TDP). The mechanism by which GRN deficiency causes TDP-43 pathology or neurodegeneration remains elusive. To explore the role of GRN in vivo, we established Grn knockout mice using a targeted genomic recombination approach and Cre-LoxP technology. Constitutive Grn homozygous knockout (Grn−/−) mice were born in an expected Mendelian pattern of inheritance and showed no phenotypic alterations compared to heterozygous (Grn+/−) or wild-type (Wt) littermates until 10 months of age. From then, Grn−/− mice showed reduced survival accompanied by significantly increased gliosis and ubiquitin-positive accumulations in the cortex, hippocampus, and subcortical regions. Although phosphorylated TDP-43 could not be detected in the ubiquitinated inclusions, elevated levels of hyperphosphorylated full-length TDP-43 were recovered from detergent-insoluble brain fractions of Grn−/− mice. Phosphorylated TDP-43 increased with age and was primarily extracted from the nuclear fraction. Grn−/− mice also showed degenerative liver changes and cathepsin D-positive foamy histiocytes within sinusoids, suggesting widespread defects in lysosomal turnover. An increase in insulin-like growth factor (IGF)-1 was observed in Grn−/− brains, and increased IGF-1 signalling has been associated with decreased longevity. Our data suggest that progranulin deficiency in mice leads to reduced survival in adulthood and increased cellular ageing accompanied by hyperphosphorylation of TDP-43, and recapitulates key aspects of FTLD-TDP neuropathology. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 115, 735-747. Null mutations in progranulin ( GRN) are associated with frontotemporal lobar degeneration characterized by intraneuronal accumulation of TAR DNA-binding protein-43 (TDP-43). However, the mechanism by which GRN deficiency leads to neurodegeneration remains largely unknown. In primary cortical neurons derived from Grn knockout (Grn−/−) mice, we found that Grn-deficiency causes significantly reduced neuronal survival and increased caspase-mediated apoptosis, which was not observed in primary mouse embryonic fibroblasts derived from Grn−/− mice. Also, neurons derived from Grn−/− mice showed an increased amount of pTDP-43 accumulations. Furthermore, proteasomal inhibition with MG132 caused increased caspase-mediated TDP-43 fragmentation and accumulation of detergent-insoluble 35- and 25-kDa C-terminal fragments in Grn−/− neurons and mouse embryonic fibroblasts. Interestingly, full-length TDP-43 also accumulated in the detergent-insoluble fraction, and caspase-inhibition prevented MG132-induced generation of TDP-43 C-terminal fragments but did not block the pathological conversion of full-length TDP-43 from soluble to insoluble species. These data suggest that GRN functions as a survival factor for cortical neurons and GRN-deficiency causes increased susceptibility to cellular stress. This leads to increased aggregation and accumulation of full-length TDP-43 along with its C-terminal derivatives by both caspase-dependent and independent mechanisms. [ABSTRACT FROM AUTHOR]