Activation of PERK signaling attenuates Abeta-mediated ER stress = Abeta에 의해 유도되는 ER stress를 억제하는 PERK

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Title
Activation of PERK signaling attenuates Abeta-mediated ER stress = Abeta에 의해 유도되는 ER stress를 억제하는 PERK
Author(s)
Do Yeon Lee; Kyu-Sun Lee; H J Lee; D H Kim; Y H Noh; Kweon Yu; H Y Jung; S H Lee; J Y Lee; Y C Youn; Y Jeong; D K Kim; W B Lee; S S Kim
Bibliographic Citation
PLoS One, vol. 5, no. 5, pp. e10489-e10489
Publication Year
2010
Abstract
Alzheimer's disease (AD) is characterized by the deposition of aggregated beta-amyloid (Abeta), which triggers a cellular stress response called the unfolded protein response (UPR). The UPR signaling pathway is a cellular defense system for dealing with the accumulation of misfolded proteins but switches to apoptosis when endoplasmic reticulum (ER) stress is prolonged. ER stress is involved in neurodegenerative diseases including AD, but the molecular mechanisms of ER stress-mediated Abeta neurotoxicity still remain unknown. Here, we show that treatment of Abeta triggers the UPR in the SK-N-SH human neuroblastoma cells. Abeta mediated UPR pathway accompanies the activation of protective pathways such as Grp78/Bip and PERK-eIF2alpha pathway, as well as the apoptotic pathways of the UPR such as CHOP and caspase-4. Knockdown of PERK enhances Abeta neurotoxicity through reducing the activation of eIF2alpha and Grp8/Bip in neurons. Salubrinal, an activator of the eIF2alpha pathway, significantly increased the Grp78/Bip ER chaperone resulted in attenuating caspase-4 dependent apoptosis in Abeta treated neurons. These results indicate that PERK-eIF2alpha pathway is a potential target for therapeutic applications in neurodegenerative diseases including AD.
ISSN
1932-6203
Publisher
Public Library of Science
DOI
http://dx.doi.org/10.1371/journal.pone.0010489
Type
Article
Appears in Collections:
Division of Biomedical Research > Disease Target Structure Research Center > 1. Journal Articles
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