Title
Increased caspase activation and decreased TDP-43 solubility in progranulin knockout cortical cultures Increased caspase activation and decreased TDP-43 solubility in progranulin knockout cortical cultures
Author
Faculty/Department
Faculty of Medicine and Health Sciences
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Publication type
article
Publication
Oxford ,
Subject
Human medicine
Source (journal)
Journal of neurochemistry. - Oxford
Volume/pages
115(2010) :3 , p. 735-747
ISSN
0022-3042
ISI
000282979400018
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
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.
E-info
https://repository.uantwerpen.be/docman/iruaauth/9dfe62/b382462c01c.pdf
https://repository.uantwerpen.be/docman/iruaauth/5ccf54/15ee5a78d26.pdf
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