Constitutive overexpression of Cu/Zn superoxide dismutase exacerbates kainic acid-induced apoptosis of transgenic-Cu/Zn superoxide dismutase neurons.

Abstract

(24).We previously investigated the possible involvement of Cu/Zn SOD overproduction in cell damage through the use of cellular and animal model systems. We found that stably transfected cells overexpressing Cu/Zn SOD exhibited substantially increased lipid peroxidation (13) and had a specific lesion that affects the chromaffin granule's proton pump, which plays an important role in the uptake of neurotransmitters into the vesicles (14). In the transgenic-Cu/Zn SOD (Tg-Cu/Zn SOD) mice, a similar defect was also identified in an analogous organelle, the platelet's dense granule, which is responsible for the uptake and storage of blood serotonin (17). It was also found that Tg-Cu/Zn SOD mice have certain thymus and bone marrow abnormalities that resemble the thymic defects in children with DS (18). These findings suggested that overexpression of Cu/Zn SOD in transgenic mice can indeed cause certain physiological abnormalities similar to those found in DS. These findings also indicated that defects caused by increased Cu/Zn SOD can have a highly specific subcellular target, and thus serve as a paradigm for how alterations in Cu/Zn SOD expression could cause oxidative stress mediated cell injury leading to neurodegenerative disease like ALS (for review, see ref. 25). In this context, it is important to note that the neuromuscular junctions of TgCu/Zn SOD mice display significant abnormalities and morphological changes including withdrawal and destruction of some terminal axons and development of multiple small terminals (15,16,26). Some of these subclinical changes are reminiscent of the pathology observed in transgenic mice with ALS-like disease, which was generated by overexpression of a mutated Cu/Zn SOD gene bearing familial ALS mutations (see ref. 25 and references therein).In the present study, we used cultured neurons from TgCu/Zn SOD mice to investigate the relation between increased expression of Cu/Zn SOD and kainic acid (KA)-induced exitotoxicity, with the aim of gaining insight into the role of altered Cu/Zn SOD expression and oxidative stress in neuronal death. MATERIALS AND METHODSTg-Cu/Zn SOD Mice and Primary Brain Cultures. Three independently produced strains of Tg-Cu/Zn SOD mice

Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor

“…Three-to six-fold overexpression of Cu/Zn SOD in transgenic mice results in increased production of H 2 O 2 and hydroxyl radicals, which accompany enhanced apoptosis of thymocytes and bone marrow cells (Peled-Kamar et al, 1995). This is similar in nature to the enhanced neurotoxicity of kainic acid by SOD overexpression that also occurs through the generation of superoxide (Bar-Peled et al, 1996). Therefore, the consequence of TCDD-induced changes in antioxidant enzyme expression is uncertain, as illustrated by the fact that up-regulation of SOD does not necessarily dictate a decrease in cellular ROS.…”

Decreased Intracellular Superoxide Levels Activate Sindbis Virus-induced Apoptosis

“…In contrast, transgenic mice overexpressing Cu,Zn-SOD appeared to have significantly fewer thymocytes and are more susceptible to lipopolysaccharide-mediated loss of thymocytes (56). Moreover, neurons derived from transgenic mice overexpressing Cu,Zn-SOD also showed higher susceptibility to kainic acid-induced apoptosis (57). Therefore, constitutive expression of a O 2 .…”

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

“…Altered free radical metabolism and impaired mitochondrial function are linked to neuronal degeneration of DS cortical neurons in culture (Busciglio and Yankner, 1995;Busciglio et al, 2002) and may be associated with both mental retardation and AD pathology in DS patients. Overexpression of several genes localized in chromosome 21 has been linked to neuronal death, including amyloid ␤ precursor protein (APP) , Cu/Zn superoxide dismutase (SOD1) (Bar-Peled et al, 1996;de Haan et al, 1996), and the transcription factor ets-2 (Wolvetang et al, 2003a). The ets family of transcription factors is involved in multiple cellular processes, including differentiation, maturation, and activation of signaling cascades (Macleod et al, 1992;Wasylyk et al, 1993).…”