Inhibition of alpha-mannosidase attenuates endoplasmic reticulum stress-induced neuronal cell death.
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 microM alpha-mannosidase inhibitor 1-deoxymannojirimycin (DMJ) in PC-12 cells significantly attenuated the cytotoxicity by ER stressors tunicamycin (TM), thapsigargin (TG), and amyloid beta1-42 (Abeta1-42), and reduced caspase-3 activation by TM and TG. Pretreatment with DMJ also protected primary cultured mouse cortical neurons from Abeta1-42 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 Abeta1-42 that causes ER stress dependent neuronal cell death. Mannopentaose (M5) and Man9GlcNAc2 (M9) oligosaccharides significantly inhibited the amyloidogenesis of Abeta1-42. 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.
Miyake
Kunio
K
Department of Epigenetic Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, 409-3898, Japan.
Nagai
Kaoru
K
D017485:1-Deoxynojirimycin / Q000494:pharmacology; D000682:Amyloid / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D006224:Cricetinae; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008358:Mannose / Q000031:analogs & derivatives; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D013312:Stress, Physiological / Q000187:drug effects*; D043323:alpha-Mannosidase / Q000037:antagonists & inhibitors*
D000682:Amyloid; D004791:Enzyme Inhibitors; D017485:1-Deoxynojirimycin; D043323:alpha-Mannosidase; D008358:Mannose