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- Title
Activation of PERK Signaling Attenuates Ab-Mediated ER Stress.
- Authors
Do Yeon Lee; Kyu-Sun Lee; Hyun Jung Lee; Do Hee Kim; Yoo Hun Noh; Kweon Yu; Hee-Yeon Jung; Sang Hyung Lee; Jun Young Lee; Young Chul Youn; Yoonhwa Jeong; Dae Kyong Kim; Won Bok Lee; Sung Su Kim
- Abstract
Alzheimer's disease (AD) is characterized by the deposition of aggregated beta-amyloid (Aβ), 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 stressmediated Aβ neurotoxicity still remain unknown. Here, we show that treatment of Aβ triggers the UPR in the SK-N-SH human neuroblastoma cells. Aβ mediated UPR pathway accompanies the activation of protective pathways such as Grp78/Bip and PERK-eIF2α pathway, as well as the apoptotic pathways of the UPR such as CHOP and caspase-4. Knockdown of PERK enhances Aβ neurotoxicity through reducing the activation of eIF2α and Grp8/Bip in neurons. Salubrinal, an activator of the eIF2α pathway, significantly increased the Grp78/Bip ER chaperone resulted in attenuating caspase-4 dependent apoptosis in Aβ treated neurons. These results indicate that PERK-eIF2α pathway is a potential target for therapeutic applications in neurodegenerative diseases including AD.
- Subjects
ALZHEIMER'S disease; AMYLOID; PROTEIN analysis; ENDOPLASMIC reticulum; NEUROTOXICOLOGY; APOPTOSIS
- Publication
PLoS ONE, 2010, Vol 5, Issue 5, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0010489