ets-2 Promotes the Activation of a Mitochondrial Death Pathway in Down's Syndrome Neurons

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␤, 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.

Deficits in human trisomy 21 iPSCs and neurons

“…2H) (DS1/4, P = 0.005; 2DS3, P = 0.03; n = 3 each). Furthermore, the increased expression of v-ets erythroblastosis virus E26 oncogene homolog 2 (ETS2), an HSA21-encoded transcription factor implicated in neuronal death and mitochondrial dysfunction (36), over the expected 1.5-fold in Ts21 neurons (Fig. 2G) prompted us to assess mitochondrial health in these cells.…”

MiR-1246: A new link of the p53 family with cancer and Down syndrome

“…Overexpression of Ets2 was found in Down syndrome patients and promoted Down syndrome-associated neuronal apoptosis. 49 The p53-dependent apoptosis was also observed in a Down syndrome mouse model with an extra copy of ets2. 49,50 Remarkably, this Down syndrome phenotype of ets2 transgenic mice was rescued by further deleting TP53, indicating that p53 is primarily responsible for the neuro-pathological phenotype in Down syndrome caused by overexpression of ets2.…”

“…However, the story might not be this simple, as some Down syndrome-associated proteins were also found to induce apoptosis in cells, such as ETS2. 49,50 Moreover, a population-based study pointed out that compared with healthy people, Down syndrome patients appear to have a lower chance to gain several common malignancies except leukemia and testicular cancer. 51 This concept has been widely accepted, largely because the statistical analysis of data came from all the Down syndrome patients who died during 1983 to 1997 in the US.…”

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

“…Alternative and sometimes complementary antioxidant pathways mediated by p53 and FOXO have been described in the context of more stringent oxidative conditions (Gorrini et al, 2013). In the case of DS cells, p53 activation is associated with an oxidative stress‐dependent mitochondrial death pathway (Wolvetang et al, 2003, Helguera et al, 2005), emphasizing the delicate balance between cytoprotective and pro‐death signals that are required to maintain cell and organismal viability. Consistent with this view, we observed significantly higher frequency of p53 translocation events in DS HF only when subjected to PQ treatment (Supporting Information Figure S6C).…”