Oxidative stress and XIAP signalling in neuronal cells
Year: 2010
Type: dissertation
Abstract: Oxidative stress is the result of an imbalance in the cellular pro-/antioxidant homeostasis which leads to the overproduction of reactive oxygen species (ROS). Usually, oxidative stress leads to structural and functional disruption within the cells, which in turn may cause cell death through different mechanisms. The brain is very sensitive to oxidative damage because of its high oxygen consumption, and oxidative stress is known to be involved e.g. in neurodegenerative diseases such as Huntington s disease (HD). X-linked Inhibitor of Apoptosis Protein (XIAP), one of the best-characterized apoptosis inhibitor proteins, is expressed both during development, and in the adult brain. Overexpression of XIAP is known to protect cells against various injuries and cell degeneration. XIAP can prevent cell death through various signalling cascades, e.g. by preventing caspases which are essential for apoptotic cell death. The function of XIAP in oxidative stress-related reactions is not that well-studied, which led us to examine it more closely. We found out that XIAP is able to reduce oxidative stress and cell death caused by ROS in vitro in neuron-like PC6.3-cells. We also noticed that XIAP increases the activation of transcription factor NFkappaB in these cells. Via NFkappaB, XIAP also increased two mitochondrial antioxidants: superoxide dismutase 2 (SOD2) and thioredoxin 2 (TRX2), and the significance of NFkappaB in this effect was also shown by using fibroblast cell lines from NFkappaB p65-/- mice. Furthermore, we observed that XIAP enhances BDNF signalling through NFkappaB in E17 hippocampal neurons. In the PC6.3-cell model of HD there was a correlation between the increased amount of ROS and the enhanced number of glutamine repeats. The protein levels of intracellular antioxidants and NFkappaB were decreased in cells expressing mutant huntingtin (htt) proteins compared to control cells. Last but not least, we observed that resveratrol (RSV) pre-treatment is able to reduce oxidative stress and cell death caused by ROS in PC6.3-cells. RSV also increased the amount of SOD2, TRX2 and XIAP, and the NFkappaB system may be involved in the increase of antioxidant proteins mediated by RSV. Altogether, these results bring us closer to understanding the role of XIAP in the control of oxidative stress and the function of XIAP in NFkappaB and BDNF signalling. In view of this, modulation of XIAP is an interesting possibility to consider in various therapies to reduce cell injuries caused by enhanced oxidative stress. RSV would also be a really interesting compound to examine as a drug candidate in disorders where oxidative stress is involved. However, studies to analyse its kinetics, actions and pharmacological and toxicological profiles are still lacking.
Source: Työväentutkimus Vuosikirja
Author: Minna Kairisalo
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1508921962