title: Bim links ER stress and apoptosis in cells expressing mutant SOD1 associated with amyotrophic lateral sclerosis.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Kai Y
authors.initials: KY
authors.lastname: Soo
authors.forename: Julie D
authors.initials: JD
authors.lastname: Atkin
authors.forename: Manal
authors.initials: M
authors.lastname: Farg
authors.forename: Adam K
authors.initials: AK
authors.lastname: Walker
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Horne
authors.forename: Phillip
authors.initials: P
authors.lastname: Nagley
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D051742:Transcription Factor CHOP / Q000378:metabolism; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D051017:Apoptosis Regulatory Proteins; C497112:Atf6 protein, mouse; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C497250:Ddit3 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C000606290:SOD1 protein, human; D051028:bcl-2-Associated X Protein; D051742:Transcription Factor CHOP; D045304:Cytochromes c; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1