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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

发布:2017-08-30约5.97万字共11页下载文档
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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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