A role for the transcription factor ets‐2 in Down's syndrome neuropathology

Abstract

Down's Syndrome (DS) is the most frequent genetic cause of mental retardation. Most DS patients develop Alzheimer's disease by middle age. A transgenic model of ets‐2 that presents pathological features similar to DS suggests a role for ets‐2 in DS (Sumarsono et al. 1996; Nature379, 534). We analyzed the expression and activity of ets‐2 in normal and DS brain tissue and human cortical neurons (HCN) in culture. Western blot and immunocytochemistry revealed that ets‐2 is expressed in the human brain and in HCN during development. The level of ets‐2 was significantly increased in DS brain homogenates and DS HCN cultures. Interestingly, DS HCN cultures exhibited reduced bcl‐2 and increased bax and p53 protein levels consistent with reduced DS neuronal viability in culture. To determine the role of ets‐2 in neuronal degeneration, normal neurons were transfected with an ets‐2 expression vector. After 24 h, a significant increase in cell death was observed in ets‐2‐transfected neurons but not in neurons cotransfected with a dominant‐negative ets‐2 expression vector (ets‐2dn). Neuronal degeneration was dependent on p53 activity since a dominant‐negative mutant form of p53 significantly abolished ets‐2‐induced neuronal degeneration. Moreover, ets‐2 overexpression did not increase neuronal death in neuronal cultures derived from p53KO mice. Finally, the expression of ets‐2dn significantly reduced degeneration of DS cortical neurons in culture. In DS, ets‐2 overexpression may compromise neuronal viability directly by inducing neuronal apoptosis or indirectly by rendering neurons more sensitive to pro‐apoptotic stimuli such as Aβ neurotoxicity and oxidative stress.