cytochrome-c-t and Down-Syndrome

Down's syndrome (DS) is characterized by a complex phenotype associated with chronic oxidative stress and mitochondrial dysfunction. Overexpression of genes on chromosome-21 is thought to underlie the pathogenesis of the major phenotypic features of DS, such as premature aging. Using cultured fibroblasts with trisomy 21 (T21F), this study aimed to ascertain whether an imbalance exists in activities, mRNA, and protein expression of the antioxidant enzymes SOD1, SOD2, glutathione-peroxidase, and catalase during the cell replication process in vitro. T21F had high SOD1 expression and activity which led to an interenzymatic imbalance in the antioxidant defense system, accentuated with replicative senescence. Intracellular ROS production and oxidized protein levels were significantly higher in T21F compared with control cells; furthermore, a significant decline in intracellular ATP content was detected in T21F. Cell senescence was found to appear prematurely in DS cells as shown by SA-β-Gal assay and p21 assessment, though not apoptosis, as neither p53 nor the proapoptotic proteins cytochrome c and caspase 9 were altered in T21F. These novel findings would point to a deleterious role of oxidatively modified molecules in early cell senescence of T21F, thereby linking replicative and stress-induced senescence in cultured cells to premature aging in DS.

Topics: Adenosine Triphosphate; Antioxidants; Caspase 9; Catalase; Cell Survival; Cells, Cultured; Cellular Senescence; Cytochromes c; Down Syndrome; Fetus; Fibroblasts; Glutathione Peroxidase; Humans; Mitochondria; Oxidative Stress; Reactive Oxygen Species; Superoxide Dismutase; Superoxide Dismutase-1; Trisomy; Tumor Suppressor Protein p53

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.

Topics: Alzheimer Disease; Animals; Apoptosis Inducing Factor; Astrocytes; bcl-2-Associated X Protein; Blotting, Western; Caspase 3; Caspases; Cell Death; Cell Survival; Cerebral Cortex; Chlorocebus aethiops; COS Cells; Cytochromes c; Diagnostic Imaging; DNA-Binding Proteins; Down Syndrome; Fetus; Fluorescent Antibody Technique; Gene Expression Regulation; Green Fluorescent Proteins; Humans; Hydrogen Peroxide; Mitochondria; Nerve Degeneration; Neurofilament Proteins; Neurons; Polycomb-Group Proteins; Protein Transport; Signal Transduction; tau Proteins; Telomerase; Time Factors; Transcription Factors; Transfection; Tumor Suppressor Protein p53