|
Title
|
|
|
|
Increased caspase activation and decreased TDP-43 solubility in progranulin knockout cortical cultures
|
|
|
Author
|
|
|
|
|
|
|
Abstract
|
|
|
|
| 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 (MEFs) derived from Grn-/- mice. Also, neurons derived from Grn-/- mice showed an increased amount of phosphorylated TDP-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 (CTFs) in Grn-/- neurons and MEFs. Interestingly, fulllength TDP-43 also accumulated in the detergent-insoluble fraction, and caspaseinhibition prevented MG132-induced generation of TDP-43 CTFs 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 GRNdeficiency 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. |
|
|
|
Language
|
|
|
|
English
|
|
|
Source (journal)
|
|
|
|
Journal of neurochemistry. - Oxford
|
|
|
Publication
|
|
|
|
Oxford
:
2010
|
|
|
ISSN
|
|
|
|
0022-3042
|
|
|
DOI
|
|
|
|
10.1111/J.1471-4159.2010.06961.X
|
|
|
Volume/pages
|
|
|
|
115
:3
(2010)
, p. 735-747
|
|
|
ISI
|
|
|
|
000282979400018
|
|
|
Full text (Publisher's DOI)
|
|
|
|
|
|
|
Full text (publisher's version - intranet only)
|
|
|
|
|
|