ets-2 promotes the activation of a mitochondrial death pathway in Down's syndrome neurons.
Down's syndrome (DS) is characterized by mental retardation and development of Alzheimer's disease (AD). Oxidative stress and mitochondrial dysfunction are both related to neurodegeneration in DS. Several genes in chromosome 21 have been linked to neuronal death, including the transcription factor ets-2. Cortical cultures derived from normal and DS fetal brains were used to study the role of ets-2 in DS neuronal degeneration. ets-2 was expressed in normal human cortical neurons (HCNs) and was markedly upregulated by oxidative stress. When overexpressed in normal HCNs, ets-2 induced a stereotyped sequence of apoptotic changes leading to neuronal death. DS HCNs exhibit intracellular oxidative stress and increased apoptosis after the first week in culture (Busciglio and Yankner, 1995). ets-2 levels were increased in DS HCNs, and, between 7 and 14 d in vitro, DS HCNs showed increased bax, cytoplasmic translocation of cytochrome c and apoptosis inducing factor, and active caspases 3 and 7, consistent with activation of an apoptotic mitochondrial death pathway. Degeneration of DS neurons was reduced by dominant-negative ets-2, suggesting that increased ets-2 expression promotes DS neuronal apoptosis. In the human brain, ets-2 expression was found in neurons and astrocytes. Strong ets-2 immunoreactivity was observed in DS/AD and sporadic AD brains associated with degenerative markers such as bax, intracellular Abeta, and hyperphosphorylated tau. Thus, in DS/AD and sporadic AD brains, converging pathological mechanisms leading to chronic oxidative stress and ets-2 upregulation in susceptible neurons may result in increased vulnerability by promoting the activation of a mitochondrial-dependent proapoptotic pathway of cell death.
Helguera
Pablo
P
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697-4550, USA.
Pelsman
Alejandra
A
Pigino
Gustavo
G
Wolvetang
Ernst
E
Head
Elizabeth
E
Busciglio
Jorge
J
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D019556:COS Cells; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000473:pathology*; D002522:Chlorocebus aethiops; D045304:Cytochromes c / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003952:Diagnostic Imaging / Q000379:methods; D004314:Down Syndrome / Q000378:metabolism* / Q000473:pathology; D005333:Fetus; D005455:Fluorescent Antibody Technique / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008928:Mitochondria / Q000502:physiology*; D009410:Nerve Degeneration / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D063146:Polycomb-Group Proteins; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019098:Telomerase / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D051033:Apoptosis Inducing Factor; D004268:DNA-Binding Proteins; D016900:Neurofilament Proteins; C112309:PHF1 protein, human; D063146:Polycomb-Group Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D016875:tau Proteins; D049452:Green Fluorescent Proteins; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D019098:Telomerase; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases
Neurosci Lett. 1999 Jan 22;260(1):9-12
10027687
J Neurochem. 2000 Jan;74(1):270-9
10617129
Am J Pathol. 2000 Jan;156(1):15-20
10623648
J Neural Transm Suppl. 1999;57:1-19
10666665
J Neural Transm Suppl. 1999;57:87-97
10666670
J Neurosci. 2001 Feb 1;21(3):834-42
11157069
Oncogene. 2000 Dec 18;19(55):6533-48
11175369
J Biol Chem. 2001 Oct 19;276(42):38388-93
11507097
Ment Retard Dev Disabil Res Rev. 2001;7(3):172-8
11553933
Biochem Biophys Res Commun. 2001 Oct 5;287(4):1003-8
11573964
JAMA. 2001 Nov 7;286(17):2120-7
11694153
J Neural Transm Suppl. 2001;(61):335-46
11771756
Cell. 2002 Jan 25;108(2):153-64
11832206
Neuron. 2002 Feb 28;33(5):677-88
11879646
Am J Psychiatry. 2002 May;159(5):738-45
11986126
Acta Neuropathol. 2002 Jul;104(1):1-6
12070657
Neuroscience. 2002;114(1):265-73
12207971
Neurosci Lett. 2002 Sep 13;330(1):99-103
12213643
Hum Mol Genet. 2003 Feb 1;12(3):247-55
12554679
Mol Cell. 2003 Mar;11(3):577-90
12667443
J Cell Biol. 2003 Apr 14;161(1):41-54
12695498
Int J Dev Neurosci. 2003 May;21(3):117-24
12711349
J Neurosci. 2003 Jun 1;23(11):4499-508
12805290
Neuron. 2003 Jul 31;39(3):409-21
12895417
J Virol. 1992 Aug;66(8):5100-5
1321290
Neurobiol Aging. 2003 Dec;24(8):1079-85
14643379
Neurobiol Dis. 2003 Dec;14(3):349-56
14678752
Neurology. 2003 Dec 23;61(12):1673-9
14694028
Cell. 2004 Jan 23;116(2):205-19
14744432
Science. 2004 Feb 13;303(5660):1010-4
14963330
Trends Biochem Sci. 1992 Jul;17(7):251-6
1502727
Cell. 1992 Aug 21;70(4):523-6
1505019
J Neurosci. 2004 Apr 7;24(14):3592-9
15071107
Science. 2004 Apr 16;304(5669):448-52
15087549
Brain Res Bull. 1986 Jun;16(6):773-87
2875770
Mech Ageing Dev. 1988 May;43(2):99-136
2969441
Proc Natl Acad Sci U S A. 1987 May;84(10):3161-5
3472202
Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7588-92
7689222
Oncogene. 1993 Nov;8(11):3005-11
8414502
Eur J Biochem. 1993 Jan 15;211(1-2):7-18
8425553
Nature. 1995 Dec 21-28;378(6559):776-9
8524410
Nature. 1996 Feb 8;379(6565):534-7
8596630
Oncogene. 1996 Mar 21;12(6):1199-1204
8649821
Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8530-5
8710904
Hum Mol Genet. 1996 Feb;5(2):283-92
8824885
Ann Neurol. 1997 Jul;42(1):85-94
9225689
Ann N Y Acad Sci. 1998 Jun 30;851:429-43
9668637