Journal
JOURNAL OF NEUROCHEMISTRY
Volume 115, Issue 3, Pages 735-747Publisher
WILEY
DOI: 10.1111/j.1471-4159.2010.06961.x
Keywords
apoptosis; cortical neurons; cell signaling; dementia; FTLD; gene knockout
Categories
Funding
- Belgian Federal Science Policy Office [P6/43]
- Medical Foundation Queen Elisabeth (GSKE)
- Foundation for Alzheimer Research (SAO/FRMA)
- Flemish Government
- Fund for Scientific Research - Flanders (FWO-V)
- University of Antwerp, Belgium
Ask authors/readers for more resources
P>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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available