Activation of PERK signaling attenuates Abeta-mediated ER stress.
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.
Lee
Do Yeon
DY
Department of Anatomy and Cell Biology, College of Medicine, Chung-Ang University, Seoul, Korea.
Lee
Kyu-Sun
KS
Lee
Hyun Jung
HJ
Kim
Do Hee
DH
Noh
Yoo Hun
YH
Yu
Kweon
K
Jung
Hee-Yeon
HY
Lee
Sang Hyung
SH
Lee
Jun Young
JY
Youn
Young Chul
YC
Jeong
Yoonhwa
Y
Kim
Dae Kyong
DK
Lee
Won Bok
WB
Kim
Sung Su
SS
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects; D019892:eIF-2 Kinase / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D002934:Cinnamates; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D034741:RNA, Small Interfering; D013890:Thiourea; D019892:eIF-2 Kinase; C000717247:HSPA5 protein, human; C496827:salubrinal
Science. 2005 Feb 11;307(5711):935-9
15705855
Neurobiol Dis. 1999 Jun;6(3):209-19
10408810
FEBS Lett. 2008 Dec 24;582(30):4185-90
19026642
Nat Cell Biol. 1999 Dec;1(8):479-85
10587643
Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7437-41
1502155
J Neurosci. 2002 Dec 15;22(24):10690-8
12486162
Trends Biochem Sci. 2001 Aug;26(8):504-10
11504627
Neurobiol Aging. 2006 Jul;27(7):973-82
15964666
Nature. 2000 Apr 13;404(6779):770-4
10783891
J Cell Biol. 2004 May 10;165(3):347-56
15123740
Cell Death Differ. 2004 Apr;11(4):381-9
14685163
Neuroscience. 2008 Aug 26;155(3):725-37
18621106
Eur J Cell Biol. 2008 Jun;87(6):389-97
18462830
J Neurosci. 2008 Jun 25;28(26):6539-48
18579727
Trends Neurosci. 2001 Nov;24(11 Suppl):S2-6
11881741
Am J Pathol. 2009 Apr;174(4):1241-51
19264902
J Biol Chem. 2002 Aug 30;277(35):32046-53
12058030
Mol Med. 1996 Nov;2(6):673-91
8972483
Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13145-50
18757748
J Neurosci. 2010 Mar 3;30(9):3326-38
20203192
Mech Ageing Dev. 2005 Dec;126(12):1292-9
16153690
Biochem J. 2007 Mar 15;402(3):581-9
17132139
Cancer Res. 2007 Apr 15;67(8):3496-9
17440054
Science. 2002 Jul 19;297(5580):353-6
12130773
Protein Sci. 1993 Mar;2(3):404-10
8453378
Nat Med. 1997 Sep;3(9):1016-20
9288729
Genes Dev. 2002 Jun 1;16(11):1307-13
12050110
J Cell Sci. 2005 Jan 1;118(Pt 1):89-99
15585578
Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14343-8
16973740
Nat Cell Biol. 2000 Jun;2(6):326-32
10854322
Nat Rev Drug Discov. 2008 Dec;7(12):1013-30
19043451
Nature. 2006 May 25;441(7092):513-7
16724068
Biochem Biophys Res Commun. 2007 Apr 6;355(2):365-70
17300747
Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20324-9
19910533
FEBS Lett. 2007 Jul 31;581(19):3641-51
17481612
J Neurosci. 2007 Jan 24;27(4):901-8
17251432
Antioxid Redox Signal. 2007 Dec;9(12):2245-54
17979527
Neurobiol Dis. 2003 Dec;14(3):567-78
14678772
J Neurochem. 2004 Mar;88(5):1140-50
15009669
Nat Cell Biol. 2008 Apr;10(4):468-75
18344986
J Biol Chem. 2001 Nov 16;276(46):43446-54
11551913
Cell Death Differ. 2006 Mar;13(3):385-92
16397584
Acta Neuropathol. 2005 Aug;110(2):165-72
15973543
Mol Cell. 2001 Jun;7(6):1165-76
11430820
Neuroscience. 2002;112(4):827-40
12088742
Neurochem Int. 2005 Oct;47(5):369-76
16005113
FASEB J. 2001 Nov;15(13):2454-62
11689470
J Neuropathol Exp Neurol. 2006 Apr;65(4):348-57
16691116
Nat Rev Immunol. 2008 Sep;8(9):663-74
18670423