TDP-43 toxicity is mediated by the unfolded protein response-unrelated induction of C/EBP homologous protein expression

✍ Scribed by Hiroaki Suzuki; Masaaki Matsuoka

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 339 KB
• Volume: 90
• Category: Article
• ISSN: 0360-4012
• DOI: 10.1002/jnr.22777

✦ Synopsis

Abstract

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/eIF2α/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. © 2011 Wiley Periodicals, Inc.