期刊
JOURNAL OF NEUROSCIENCE RESEARCH
卷 90, 期 3, 页码 641-647出版社
WILEY
DOI: 10.1002/jnr.22777
关键词
ALS; FTLD-U; TDP-43; CHOP
资金
- Japan Society for the Promotion of Science [20390072, 22790261]
- Ministry of Education, Culture, Sports, Science, and Technology (MEXT)
- Grants-in-Aid for Scientific Research [22790261, 20390072] Funding Source: KAKEN
Transactive response DNA-binding protein-43 (TDP-43) neuronal toxicity plays an essential role in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclusions. In our previous study, we showed that low-grade overexpression of TDP-43, which is thought to mimic the gain-of-function of TDP-43, caused neuronal death, mediated by the upregulation of Bim and the downregulation of Bcl-xL in vitro. In this study, we show that TDP-43 overexpression caused the upregulation of C/EBP-homologous protein (CHOP) and that disruption of the CHOP gene markedly attenuated TDP-43-induced cell death. These results indicate that increases in CHOP expression contribute to TDP-43-induced cell death. We also show that the TDP-43-induced upregulation of CHOP expression is mediated by both the upregulation of the mRNA level of CHOP and the attenuation of thedegradation of CHOP, which is independent on the PERK/eIF2a/ATF4 or other pathway related to the unfolded protein response (UPR) to endoplasmic reticulum stress. This study provides the first example of the CHOP-mediated cell death that is independent of the UPR. (c) 2011 Wiley Periodicals, Inc.
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