Increased caspase activation and decreased TDP-43 solubility in progranulin knockout cortical cultures

J Neurochem. 2010 Nov;115(3):735-47. doi: 10.1111/j.1471-4159.2010.06961.x. Epub 2010 Sep 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Blotting, Western
  • Caspases / metabolism*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism*
  • Enzyme Activation / physiology
  • Fibroblasts / metabolism
  • Granulins
  • Immunohistochemistry
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Oncogene Protein v-akt / metabolism
  • Phosphorylation
  • Progranulins
  • Proteasome Endopeptidase Complex
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction


  • DNA-Binding Proteins
  • Granulins
  • Grn protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Progranulins
  • Recombinant Proteins
  • Oncogene Protein v-akt
  • Caspases
  • Proteasome Endopeptidase Complex