bim links er stress and apoptosis in cells expressing mutant sod1 associated with amyotrophic lateral sclerosisbim链接er应激和凋亡细胞中表达sod1基因突变与肌萎缩性脊髓侧索硬化症有关.pdf
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Bim Links ER Stress and Apoptosis in Cells Expressing
Mutant SOD1 Associated with Amyotrophic Lateral
Sclerosis
1,2 2,3,4 2 2,3,4¤ 3,4,5 1
Kai Y. Soo , Julie D. Atkin , Manal Farg , Adam K. Walker , Malcolm K. Horne , Phillip Nagley *
1 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia, 2 Department of Biochemistry, La Trobe Institute of Molecular
Science, La Trobe University, Bundoora, Victoria, Australia, 3 Florey Neuroscience Institutes, University of Melbourne, Parkville, Victoria, Australia, 4 Centre for
Neuroscience, University of Melbourne, Parkville, Victoria, Australia, 5 Department of Neurology, St Vincent’s Hospital, Fitzroy, Victoria, Australia
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
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