title: TDP-43 toxicity is mediated by the unfolded protein response-unrelated induction of C/EBP homologous protein expression.
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.
authors: Department of Pharmacology, Tokyo Medical University, Tokyo, Japan.
authors: Hiroaki
authors: H
authors: Suzuki
authors: Masaaki
authors: M
authors: Matsuoka
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D051379:Mice; D015398:Signal Transduction / Q000235:genetics; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; D051742:Transcription Factor CHOP