A recent paper published in Cell Stem Cell reminds us that things are not always as they seem in biology. Autism Speaks’ funded projects led by co-authors Dr. Harley Kornblum and Dr. Janel Le Belle revealed that reactive oxygen species (ROS)—the cellular culprits creating oxidative stress—are actually necessary and present at higher levels early in the lives of brain cells.
Reactive oxygen species are a byproduct of normal cell metabolism. They can be damaging due to their chemically unstable nature. Peroxides are examples of ROS that result from the normal energy-production processes that take place inside the mitochondria in each cell. Typically, cells have a host of enzymes and cellular antioxidants to defend against an accumulation of ROS. However, environmental stressors such as ultraviolet radiation or overexposure to toxins can create more ROS than can be managed by an adult brain cell.
The research team was able to observe how young neurons not only used ROS to signal changes in cell processes, but needed more as they grew from neural stem cells into new neurons in the developing animal or human. Previously, it was believed that stem cells maintained low levels of ROS to protect the cells from damage, but neural stem cells seem to actually need higher levels of ROS to go on and make new neurons.
Certainly this is not the first time ROS has been shown to create positive effects. Previous research has shown that ROS can trigger the release of defense mechanisms against pathogens and initiate wound repair. However, more often, the build-up of ROS in cells is linked with cognitive decline in aging animals, when cellular mechanisms are less effective at removing ROS.
Other recent research has shown that by deleting genes that protect against a substantial increase in ROS, the young cells grow too much or “hyperproliferate”. The result is early brain overgrowth, much like has been reported for young children with autism. We don’t yet know at what stage in human fetal development higher levels of ROS would lead to larger brains, but this is one of many next stages of study in this line of questioning. From the studies in this report, it seems that the conversion of neural stem cells to differentiated neurons requires increased ROS, and suppressing it by various means also suppresses the creation of the new neurons from their stem cell predecessors.
Although the details of the “when” are as yet unknown with respect to early brain overgrowth due to increased ROS, the “how” is better understood. The pathway that leads to overgrowth is part of the well-studied PTEN pathway. We know a good bit about the molecular cascades in this pathway because the single gene mutations responsible for Tuberous Sclerosis complex (TSC)—one of the single gene disorders with a high proportion of individuals presenting with autism. PTEN acts as a suppressor of a pathway that encourages growth and the proliferation of new cells. Interestingly, Dr. Kornblum and his team showed that when ROS levels are reduced in developing brains, this pathway is less active and fewer new neurons are produced. Too much ROS leads to hyperproliferation and too little reduces the number of new cells produced.
This new research underscores the important role of ROS in the developing brain; however it is not yet clear whether antioxidant therapy would be beneficial or harmful during normal development or even in the fetuses at higher risk for autism. However, this is something that Dr. Kornblum and his team hope to explore, saying “The key here is that we cannot think of antioxidants as either universally good or universally bad.”
Janel E. Le Belle, Nicolas M. Orozco, Andres A. Paucar, Jonathan P. Saxe, Jack Mottahedeh, April D. Pyle, Hong Wu, and Harley I. Kornblum. (2011) Cell Stem Cell. Proliferative Neural Stem Cells Have High Endogenous ROS Levels that Regulate Self-Renewal and Neurogenesis in a PI3K/Akt-Dependant Manner. 8: 59–71. DOI 10.1016/j.stem.2010.11.028