Cytoplasmic accumulation and aggregation of TDP-43 upon proteasome inhibition in cultured neurons

van Eersel, Janet, Ke, Yazi D., Gladbach, Amadeus, Bi, Mian, Gotz, Jurgen, Kril, Jillian J. and Ittner, Lars M. (2011) Cytoplasmic accumulation and aggregation of TDP-43 upon proteasome inhibition in cultured neurons. PLoS ONE, 6 7: e22850.1-e22850.13. doi:10.1371/journal.pone.0022850


Author van Eersel, Janet
Ke, Yazi D.
Gladbach, Amadeus
Bi, Mian
Gotz, Jurgen
Kril, Jillian J.
Ittner, Lars M.
Title Cytoplasmic accumulation and aggregation of TDP-43 upon proteasome inhibition in cultured neurons
Journal name PLoS ONE   Check publisher's open access policy
ISSN 1932-6203
Publication date 2011-07-01
Year available 2011
Sub-type Article (original research)
DOI 10.1371/journal.pone.0022850
Open Access Status DOI
Volume 6
Issue 7
Start page e22850.1
End page e22850.13
Total pages 13
Place of publication San Francisco United States
Publisher Public Library of Science (PLoS)
Language eng
Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterized by intraneuronal deposition of the nuclear TAR DNA-binding protein 43 (TDP-43) caused by unknown mechanisms. Here, we studied TDP-43 in primary neurons under different stress conditions and found that only proteasome inhibition by MG-132 or lactacystin could induce significant cytoplasmic accumulation of TDP-43, a histopathological hallmark in disease. This cytoplasmic accumulation was accompanied by phosphorylation, ubiquitination and aggregation of TDP-43, recapitulating major features of disease. Proteasome inhibition produced similar effects in both hippocampal and cortical neurons, as well as in immortalized motor neurons. To determine the contribution of TDP-43 to cell death, we reduced TDP-43 expression using small interfering RNA (siRNA), and found that reduced levels of TDP-43 dose-dependently rendered neurons more vulnerable to MG-132. Taken together, our data suggests a role for the proteasome in subcellular localization of TDP-43, and possibly in disease.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
 
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