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Activation of PERK signaling attenuates Abeta-mediated ER stress.

Lee do Y, Lee KS, Lee HJ, Kim do H, Noh YH, Yu K, Jung HY, Lee SH, Lee JY, Youn YC, Jeong Y, Kim DK, Lee WB, Kim SS - PLoS ONE (2010)

Bottom Line: Here, we show that treatment of Abeta triggers the UPR in the SK-N-SH human neuroblastoma cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, College of Medicine, Chung-Ang University, Seoul, Korea.

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.

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PERK siRNA reduces the neuronal cell viability by Aβ treatment.A, PERK siRNA transfection was confirmed by the PERK RT-PCR analysis. B, The cell viability in PERK siRNA transfection with Aβ treatment was reduced compared with Aβ treatment alone. Data were presented as means ± SD from at least three independent experiments. C, PERK siRNA transfection with Aβ treatment suppressed the activated eIF2α and Grp78/Bip by Aβ treatment alone. *P<0.05, control siRNA + Aβ versus PERK siRNA + Aβ.
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pone-0010489-g003: PERK siRNA reduces the neuronal cell viability by Aβ treatment.A, PERK siRNA transfection was confirmed by the PERK RT-PCR analysis. B, The cell viability in PERK siRNA transfection with Aβ treatment was reduced compared with Aβ treatment alone. Data were presented as means ± SD from at least three independent experiments. C, PERK siRNA transfection with Aβ treatment suppressed the activated eIF2α and Grp78/Bip by Aβ treatment alone. *P<0.05, control siRNA + Aβ versus PERK siRNA + Aβ.

Mentions: To elucidate the role of PERK-eIF2α pathway in ER stress-mediated neuronal cell death by Aβ treatment, we knocked down expression of PERK by using siRNA against PERK. Transfection of PERK siRNA, but not control siRNA significantly reduced endogenous PERK mRNA levels (Fig. 3A). We then have assessed the role of PERK on ER stress mediated Aβ neurotoxicity. When treated with Aβ in SK-N-SH cells, silencing of PERK showed slightly enhanced cell death in comparison with those transfected with the control siRNA (Fig. 3B). These results indicate that PERK may play a role in cell survival mechanism rather than apoptosis on ER stress mediated Aβ neurotoxicity.


Activation of PERK signaling attenuates Abeta-mediated ER stress.

Lee do Y, Lee KS, Lee HJ, Kim do H, Noh YH, Yu K, Jung HY, Lee SH, Lee JY, Youn YC, Jeong Y, Kim DK, Lee WB, Kim SS - PLoS ONE (2010)

PERK siRNA reduces the neuronal cell viability by Aβ treatment.A, PERK siRNA transfection was confirmed by the PERK RT-PCR analysis. B, The cell viability in PERK siRNA transfection with Aβ treatment was reduced compared with Aβ treatment alone. Data were presented as means ± SD from at least three independent experiments. C, PERK siRNA transfection with Aβ treatment suppressed the activated eIF2α and Grp78/Bip by Aβ treatment alone. *P<0.05, control siRNA + Aβ versus PERK siRNA + Aβ.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2864758&req=5

pone-0010489-g003: PERK siRNA reduces the neuronal cell viability by Aβ treatment.A, PERK siRNA transfection was confirmed by the PERK RT-PCR analysis. B, The cell viability in PERK siRNA transfection with Aβ treatment was reduced compared with Aβ treatment alone. Data were presented as means ± SD from at least three independent experiments. C, PERK siRNA transfection with Aβ treatment suppressed the activated eIF2α and Grp78/Bip by Aβ treatment alone. *P<0.05, control siRNA + Aβ versus PERK siRNA + Aβ.
Mentions: To elucidate the role of PERK-eIF2α pathway in ER stress-mediated neuronal cell death by Aβ treatment, we knocked down expression of PERK by using siRNA against PERK. Transfection of PERK siRNA, but not control siRNA significantly reduced endogenous PERK mRNA levels (Fig. 3A). We then have assessed the role of PERK on ER stress mediated Aβ neurotoxicity. When treated with Aβ in SK-N-SH cells, silencing of PERK showed slightly enhanced cell death in comparison with those transfected with the control siRNA (Fig. 3B). These results indicate that PERK may play a role in cell survival mechanism rather than apoptosis on ER stress mediated Aβ neurotoxicity.

Bottom Line: Here, we show that treatment of Abeta triggers the UPR in the SK-N-SH human neuroblastoma cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, College of Medicine, Chung-Ang University, Seoul, Korea.

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.

Show MeSH
Related in: MedlinePlus