Inhibition of alpha-mannosidase attenuates endoplasmic reticulum stress-induced neuronal cell death.
Neurotoxicology
; 30(1): 144-50, 2009 Jan.
Article
em En
| MEDLINE
| ID: mdl-19028522
ABSTRACT
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.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Estresse Fisiológico
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Alfa-Manosidase
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Retículo Endoplasmático
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Neurônios
Limite:
Animals
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article