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Cellular ageing, increased mortality and FTLD-TDP-associated neuropathology in progranulin knockout mice.

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.

Pubmed ID: 22733568


  • Wils H
  • Kleinberger G
  • Pereson S
  • Janssens J
  • Capell A
  • Van Dam D
  • Cuijt I
  • Joris G
  • De Deyn PP
  • Haass C
  • Van Broeckhoven C
  • Kumar-Singh S


The Journal of pathology

Publication Data

September 31, 2012

Associated Grants


Mesh Terms

  • Animals
  • Behavior, Animal
  • Brain
  • Cell Aging
  • DNA-Binding Proteins
  • Female
  • Frontotemporal Lobar Degeneration
  • Gene Expression
  • Gliosis
  • Intercellular Signaling Peptides and Proteins
  • Liver
  • Longevity
  • Male
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Survival Rate
  • Ubiquitin