An excess of a natural molecule can bring about the devastating -water on the brain- condition in mice and blocking its action can prevent the effect
Scientists at The Scripps Research Institute have found what may be a major cause of congenital hydrocephalus, one of the most common neurological disorders of childhood that produces mental debilitation and sometimes death in premature and newborn children.
The research appears in the September 7, 2011, issue of the journal Science Translational Medicine.
Hydrocephalus, which involves excess buildup of cerebrospinal fluid in the brain, affects about 1 in 500 children in the United States. Currently only symptomatic treatment exists-the surgical placement of a shunt to drain away excess fluid. Researchers want to know the condition's causes, so they can figure out how to prevent and treat it. Scientists have known for some time that hydrocephalus was linked to bleeding events in the developing brain, but the reason for that linkage has not been clear.
The new study now suggests that hydrocephalus can be triggered by abnormal levels of lysophosphatidic acid (LPA), a blood-borne lipid that can enter the brain in high concentrations during bleeding events, with profound effects on developing brain cells. The study showed that both blood and LPA itself acted through the same receptor (receptors are proteins to which one or more specific kinds of signaling molecules bind) to produce defects in the brains of developing mice that led to severe hydrocephalus; genetic removal of a specific LPA receptor or pre-treatment with a compound that blocked the receptor largely prevented the condition.
"This provides proof of concept for the medical treatment of this disease," said Jerold Chun, MD, PhD, a professor at Scripps Research and its Dorris Neuroscience Center, and senior author of the new study, "and it also hints that this mechanism involving LPA could be relevant to other neurological conditions associated with altered brain development."
A Eureka Moment
Chun's laboratory specializes in the study of lipid-signaling molecules involved in the developing brain, including LPA. LPA is normally produced in the fast-growing fetal brain, and appears to be important for the normal development of neural "progenitor" cells. But when the researchers added abnormally high concentrations of LPA to the brains of fetal mice, they found an unexpected effect on brain development. "When we looked at their condition as newborns, we were surprised to see that they uniformly had big, fluid-filled brains," said postdoctoral fellow Yun Yung, PhD. "It was a Eureka moment, because we realized that LPA might help explain hydrocephalus."
Reviewing the medical literature on the condition, Chun and Yung noted that it was often linked to brain-bleeding events in the womb and typically also featured some improperly developed brain structures. "Our experiments with LPA connected both sets of findings," said Yung, "because LPA is involved in blood clotting and can reach very high concentrations during hemorrhages; plus, our LPA-exposed mouse brains had structural abnormalities like those reported in human cases."
Cerebrospinal fluid cushions the brain, provides it with basic nutrients, and is normally produced by the membrane-like choroid plexus within the fluid-filled chambers of the brain known as ventricles. Ependymal cells that line these ventricles have hair-like extensions that are thought to promote the normal flow of fluid. "In our LPA-exposed mice, there were patches in the ventricular lining where these ependymal cells were missing, which could have led to a disruption of the normal cerebrospinal fluid flow," said Yung. Structures in the ventricles that normally permit the proper drainage of fluid also appeared to be partly blocked by the improper overgrowth of cells, which might have further contributed to the brain-damaging fluid buildup.