s occurs in some cases of autism."
The body has a system to make ROS when it needs it. Some cells, such as immune cells, surround bacteria or viruses and use ROS to kill the invading microbes. Outside influences such as stress and environmental factors such as exposure to radiation can increase ROS levels in cells.
Although ROS is produced by all cells in a passive manner as a by-product of normal cell metabolism, some cells also produce ROS in a directed manner using ROS-producing enzymes like NADPH oxidase (NOX). NOX-generated ROS can act as second messengers in tightly controlled signal transduction pathways for many growth and trophic factors. However, too much ROS damages and ultimately kills cells, so finding the correct balance is vital, Kornblum said. And in fact, when the neural stem cells in the study were given too much ROS, they did die.
Kornblum and his team also found that the ROS-mediated stem cell self-renewal and differentiation of these cells into neurons depended on a cell signaling pathway called PI3K/Akt, which is known to be involved in cellular functions such as cell growth, proliferation, differentiation, motility and survival. NOX-generated ROS affect PI3K/Akt signaling by causing the inactivation of the PTEN protein, an important tumor suppressor and negative regulator of the pathway, by oxidizing a cysteine residue in the protein, which inactivates its function.
Kornblum and his collaborators at UCLA, including Dr. Hong Wu, a professor of molecular and medical pharmacology and a co-author of the study, have been studying the PI3K pathway for years. The pathway is activated in some diseases, for example a subset of autism cases and in tuberous sclerosis, a rare, multi-system genetic disease that causes non-malignant tumors to grow in the brain and in other vital organs. The pathway also can be activated in certain cancers.
"One of our hypotheses is that in these disease states, for instance in autism, that in those with a genetic predisposition to PI3K activation, exposure to a stressor that increases ROS levels can exacerbate the predisposition, perhaps promoting the disease," Kornblum said.
In brain tumors, if the pathway gets activated in cells already susceptible to becoming cancerous, it may promote the proliferation of brain tumor cells or the propagation of brain tumors. Blocking the pathway, Kornblum said, may be one way to interrupt the malignant process.
Going forward, Kornblum and his team will seek to determine whether brain cancer cells use elevated ROS and the PI3K pathway to promote their own growth. Le Belle said they will also test whether elevated ROS during brain development can contribute to brain overgrowth in Autism. Additionally, the team will test to see if they can exploit the ROS-activated pathway to promote brain repair, for example, increasing the production of new neurons to replace damaged or dead neurons.
On the Net: