ets-2 promotes the activation of a mitochondrial death pathway in Down's syndrome neurons

Helguera, Pablo, Pelsman, Alejandra, Pigino, Gustavo, Wolvetang, Ernst, Head, Elizabeth and Busciglio, Jorge (2005) ets-2 promotes the activation of a mitochondrial death pathway in Down's syndrome neurons. Journal of Neuroscience, 25 9: 2295-2303. doi:10.1523/JNEUROSCI.5107-04.2005

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Author Helguera, Pablo
Pelsman, Alejandra
Pigino, Gustavo
Wolvetang, Ernst
Head, Elizabeth
Busciglio, Jorge
Title ets-2 promotes the activation of a mitochondrial death pathway in Down's syndrome neurons
Journal name Journal of Neuroscience   Check publisher's open access policy
ISSN 0270-6474
Publication date 2005-03-02
Sub-type Article (original research)
DOI 10.1523/JNEUROSCI.5107-04.2005
Open Access Status File (Publisher version)
Volume 25
Issue 9
Start page 2295
End page 2303
Total pages 9
Place of publication Washington, DC, United States
Publisher Society for Neuroscience
Language eng
Subject 060103 Cell Development, Proliferation and Death
060109 Proteomics and Intermolecular Interactions (excl. Medical Proteomics)
Abstract 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 A{beta}, 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.
Keyword Down's syndrome
Alzheimer's disease
oxidative stress
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ

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Created: Thu, 12 Feb 2009, 10:32:11 EST by Judy Dingwall on behalf of Aust Institute for Bioengineering & Nanotechnology