Inhibition of α-mannosidase attenuates endoplasmic reticulum stress-induced neuronal cell death

被引:8
作者
Miyake, Kunio [1 ]
Nagai, Kaoru [1 ]
机构
[1] Univ Yamanashi, Interdisciplinary Grad Sch Med & Engn, Dept Epigenet Med, Yamanashi 4093898, Japan
关键词
1-Deoxymannojirimycin; N-glycosylation; Amyloid beta; ER stress; Apoptosis; UNFOLDED PROTEIN RESPONSE; CHAPERONE-LIKE FUNCTIONS; N-GLYCANS; MOLECULAR CHAPERONE; ER; OLIGOSACCHARIDES; GLYCOSYLATION; APOPTOSIS; TRANSPORT; ACID;
D O I
10.1016/j.neuro.2008.10.010
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
N-glycosylation is crucial for proper folding of most of the proteins in the endoplasmic reticulum (ER). The N-glycans in the ER are mainly constructed of mannose. In this study, we examined whether inhibition of mannose trimming in the ER affects the susceptibility of PC-12 cells to ER stress. Pretreatment with 100 mu M alpha-mannosidase inhibitor 1-deoxymannojirimycin (DMJ) in PC-12 cells significantly attenuated the cytotoxicity by ER stressors tunicamycin (TM), thapsigargin (TG), and amyloid beta 1-42 (A beta 1-42), and reduced caspase-3 activation by TM and TG. Pretreatment with DMJ also protected primary cultured mouse cortical neurons from A beta 1-42 toxicity. With regard to the effect of DMJ pretreatment on ER stress signaling in PC-12 cells, DMJ attenuated TM- and TG-induced CHOP expression and TG stimulated JNK phosphorylation, which is associated with ER stress dependent cell death. Next, we examined the effect of mannose oligosaccharides, which have similar structures to N-glycans in the ER, on amyloidogenesis of A beta 1-42 that causes ER stress dependent neuronal cell death. Mannopentaose (M5) and Man(9)GlcNAc(2) (M9) oligosaccharides significantly inhibited the amyloidogenesis of A beta 1-42. Our data suggests that inhibition of N-glycan processing in the ER attenuates ER stress-induced cell death by increasing high-mannose type oligosaccharides that reduce protein aggregation, such as amyloidogenesis. (C) 2008 Elsevier Inc. All rights reserved.
引用
收藏
页码:144 / 150
页数:7
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