Bim links ER stress and apoptosis in cells expressing mutant SOD1 associated with amyotrophic lateral sclerosis

Kai Y. Soo, Julie D. Atkin, Manal Farg, Adam K. Walker, Malcolm K. Horne, Phillip Nagley

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Endoplasmic reticulum (ER) stress is an important pathway to cell death in amyotrophic lateral sclerosis (ALS). We previously demonstrated that ER stress is linked to neurotoxicity associated with formation of inclusions of mutant Cu,Zn-superoxide dismutase 1 (SOD1). Cells bearing mutant inclusions undergo mitochondrial apoptotic signalling. Here, we demonstrate that the BH3-only protein, Bim, is a direct link between ER stress and mitochondrial apoptosis. In the murine neuroblastoma cell line, Neuro2a, bearing mutant SOD1 inclusions, indicators of both ER stress and apoptosis are expressed. Bim knockdown by siRNA significantly reduced nuclear apoptotic features in these inclusion-bearing cells (but did not affect the proportion of cells overall that bear inclusions). Further, both Bax recruitment to mitochondria and cytochrome c redistribution were also decreased under Bim-depletion conditions. However, upregulation of CHOP, a marker of ER stress, was not reduced by Bim knockdown. Significantly, knockdown of CHOP by siRNA reduced the extent of apoptosis in cells bearing mutant SOD1 inclusions. These sequential links between ER stress, CHOP upregulation, and Bim activation of mitochondrial apoptotic signalling indicate a clear pathway to cell death mediated by mutant SOD1.

LanguageEnglish
Article numbere35413
Pages1-11
Number of pages11
JournalPLoS ONE
Volume7
Issue number4
DOIs
Publication statusPublished - 16 Apr 2012
Externally publishedYes

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Endoplasmic Reticulum Stress
Amyotrophic Lateral Sclerosis
Bearings (structural)
endoplasmic reticulum
Superoxide Dismutase
superoxide dismutase
apoptosis
Cells
Apoptosis
mutants
Cell death
cells
small interfering RNA
Small Interfering RNA
cell death
Cell Death
Up-Regulation
Mitochondria
neurotoxicity
cytochrome c

Cite this

Soo, Kai Y. ; Atkin, Julie D. ; Farg, Manal ; Walker, Adam K. ; Horne, Malcolm K. ; Nagley, Phillip. / Bim links ER stress and apoptosis in cells expressing mutant SOD1 associated with amyotrophic lateral sclerosis. In: PLoS ONE. 2012 ; Vol. 7, No. 4. pp. 1-11.
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abstract = "Endoplasmic reticulum (ER) stress is an important pathway to cell death in amyotrophic lateral sclerosis (ALS). We previously demonstrated that ER stress is linked to neurotoxicity associated with formation of inclusions of mutant Cu,Zn-superoxide dismutase 1 (SOD1). Cells bearing mutant inclusions undergo mitochondrial apoptotic signalling. Here, we demonstrate that the BH3-only protein, Bim, is a direct link between ER stress and mitochondrial apoptosis. In the murine neuroblastoma cell line, Neuro2a, bearing mutant SOD1 inclusions, indicators of both ER stress and apoptosis are expressed. Bim knockdown by siRNA significantly reduced nuclear apoptotic features in these inclusion-bearing cells (but did not affect the proportion of cells overall that bear inclusions). Further, both Bax recruitment to mitochondria and cytochrome c redistribution were also decreased under Bim-depletion conditions. However, upregulation of CHOP, a marker of ER stress, was not reduced by Bim knockdown. Significantly, knockdown of CHOP by siRNA reduced the extent of apoptosis in cells bearing mutant SOD1 inclusions. These sequential links between ER stress, CHOP upregulation, and Bim activation of mitochondrial apoptotic signalling indicate a clear pathway to cell death mediated by mutant SOD1.",
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Bim links ER stress and apoptosis in cells expressing mutant SOD1 associated with amyotrophic lateral sclerosis. / Soo, Kai Y.; Atkin, Julie D.; Farg, Manal; Walker, Adam K.; Horne, Malcolm K.; Nagley, Phillip.

In: PLoS ONE, Vol. 7, No. 4, e35413, 16.04.2012, p. 1-11.

Research output: Contribution to journalArticleResearchpeer-review

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