PMID- 19028522
OWN - NLM
STAT- MEDLINE
DCOM- 20090413
LR  - 20131121
IS  - 0161-813X (Print)
IS  - 0161-813X (Linking)
VI  - 30
IP  - 1
DP  - 2009 Jan
TI  - Inhibition of alpha-mannosidase attenuates endoplasmic reticulum stress-induced 
      neuronal cell death.
PG  - 144-50
LID - 10.1016/j.neuro.2008.10.010 [doi]
AB  - 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.
FAU - Miyake, Kunio
AU  - Miyake K
AD  - Department of Epigenetic Medicine, Interdisciplinary Graduate School of Medicine 
      and Engineering, University of Yamanashi, Yamanashi, 409-3898, Japan.
FAU - Nagai, Kaoru
AU  - Nagai K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20081106
PL  - Netherlands
TA  - Neurotoxicology
JT  - Neurotoxicology
JID - 7905589
RN  - 0 (Amyloid)
RN  - 0 (Enzyme Inhibitors)
RN  - 19130-96-2 (1-Deoxynojirimycin)
RN  - EC 3.2.1.24 (alpha-Mannosidase)
RN  - PHA4727WTP (Mannose)
SB  - IM
MH  - 1-Deoxynojirimycin/pharmacology
MH  - Amyloid/antagonists & inhibitors/biosynthesis
MH  - Animals
MH  - Cell Death/drug effects
MH  - Cell Line, Transformed
MH  - Cells, Cultured
MH  - Cricetinae
MH  - Endoplasmic Reticulum/*metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Mannose/analogs & derivatives
MH  - Mice
MH  - Neurons/*metabolism
MH  - Rats
MH  - Stress, Physiological/*drug effects
MH  - alpha-Mannosidase/*antagonists & inhibitors
EDAT- 2008/11/26 09:00
MHDA- 2009/04/14 09:00
CRDT- 2008/11/26 09:00
PHST- 2008/07/29 00:00 [received]
PHST- 2008/10/16 00:00 [revised]
PHST- 2008/10/19 00:00 [accepted]
PHST- 2008/11/26 09:00 [entrez]
PHST- 2008/11/26 09:00 [pubmed]
PHST- 2009/04/14 09:00 [medline]
AID - S0161-813X(08)00193-9 [pii]
AID - 10.1016/j.neuro.2008.10.010 [doi]
PST - ppublish
SO  - Neurotoxicology. 2009 Jan;30(1):144-50. doi: 10.1016/j.neuro.2008.10.010. Epub 
      2008 Nov 6.