Potential pathway for drug intervention

Mar 13, 2009
The top image shows neural precursor cells generate glial cells (shown in green) after being stimulated with retinoic acid or cytokines. The bottom image shows neural precursor cells making more synaptojanin-1 protein produce more glial cells. Courtesy of Dr. Federico Herrera, Salk Institute for Biological Studies

A newly identified molecular pathway that directs stem cells to produce glial cells yields insights into the neurobiology of Down's syndrome and a number of central nervous system disorders characterized by too many glial cells, according to a recent study by researchers at the Salk Institute for Biological Studies.

Their findings, to be published in the March 13 online edition of Cell Death and Differentiation, indicate that synaptojanin-1, a central component of the pathway, is essential to production of glia, that act as neurons' personal assistants. Down's syndrome, spinal cord injury, Alzheimer's disease, and stroke all are linked by an overproduction of glia. Understanding this molecular pathway may also have implications for the onset of glioblastoma, the most common and malignant type of brain tumor.

With the relevance of glia to human function and pathology already widely accepted, Salk professor David Schubert, who heads the Cellular Neurobiology Laboratory, observes: "The discovery of this molecular signaling pathway promises to completely change the way we think about central nervous system maladies, allowing the development of drugs that inhibit glial proliferation and improve the prognosis of patients with a host of devastating conditions."

Down´s syndrome is the most frequent cause of mental retardation, with an incidence of 1 of every 800 births. Cognitive deficits, as well as changes in the basic composition of the brain, are observed soon after birth, reflecting problems in brain development. Although it is known that Down's syndrome is caused by an extra copy of , the exact genetic details largely remain a mystery.

Among the established anomalies found in the brains of Down´s syndrome patients are a greater than normal number of glial cells and perhaps fewer nerve cells. The reason for these characteristics has been unclear, however. Using a new mass spectrometry technique and stem cells that can be made to produce either neurons or glia, a team of Salk researchers led by first author Federico Herrera, Ph.D., a senior scientist in the Cellular Neurobiology Laboratory, identified a molecular signaling pathway that is required for the production of glial cells.

He and his colleagues then sought to determine whether the pathway was more active in Down's syndrome patients and a mouse model of the condition. What they found was that the level of a protein called synaptojanin-1, which is encoded in chromosome 21, is much higher in both and is strongly correlated with a greater number of glial cells.

"Given the required balance between the numbers of neurons and glia in a normal brain, an excess of glia may contribute to the cognitive deficits that characterize Down´s syndrome," says Herrera. The team also found that Synaptojanin-1 was not required for the production of neurons, and they identified the particular part of the Synaptojanin-1 molecule that was responsible for generating glia. "This is a critical first step to identifying drugs that specifically block the excess proliferation of glial cells associated with Down´s syndrome and perhaps promote the production of more neurons," Herrera adds.

Furthermore, the medical implications of this discovery extend beyond Down's syndrome. According to Schubert, a surplus of glial cells is detrimental to the regeneration of nerves following spinal injury. "It is thought that the aberrant accumulation of glial cells around the site of spinal injury, the so-called glial scar, actively inhibits nerve regeneration," he says.

Increased production of glial cells is frequently seen in other conditions as well, including stroke and neurodegenerative disorders such as Alzheimer´s disease, and may contribute to the brain damage associated with them. Interestingly, a large proportion of Down´s syndrome patients develop Alzheimer´s disease at a young age, and Herrera believes that a higher proportion of glial cells could be a contributing factor.

Abnormal production of glia is also implicated in glioblastoma, the most common and malignant of brain tumors, which is thought to be caused by the inappropriate generation of glia from brain stem cells. While normal glia only proliferate when the brain suffers some kind of injury, the defective glia found in glioblastomas proliferate spontaneously. "In this case, our findings could be used to transform tumor cells into normal glia," says Herrera.

Source: Salk Institute (news : web)

Explore further: Researchers find animals killed by anthrax leave behind enticing grasses for herbivores, allowing disease to spread

add to favorites email to friend print save as pdf

Related Stories

Milestone in the regeneration of brain cells

Aug 20, 2007

The majority of cells in the human brain are not nerve cells but star-shaped glia cells, the so called “astroglia”. “Glia means “glue”, explains Götz. “As befits their name, until now these cells have been regarded ...

Without glial cells, animals lose their senses

Oct 30, 2008

(PhysOrg.com) -- Sensory neurons have always put on a good show. But now, it turns out, they'll be sharing the credit. In groundbreaking research to appear in the October 31 issue of Science, Rockefeller Univer ...

Glia guide brain development in worms

Jul 14, 2008

Again and again, experiments confirmed it. Without glia, neurons die. So scientists who wanted to study in living animals what glia — the most abundant brain cells — do for neurons besides keep them alive ...

Recommended for you

What happens when good genes get lost?

15 hours ago

Scientifically speaking, there is no bad DNA, though we like to blame it for unruly hair, klutziness or poor gardening skills. There is, however, junk DNA.

Plants prepackage beneficial microbes in their seeds

Sep 29, 2014

Plants have a symbiotic relationship with certain bacteria. These 'commensal' bacteria help the pants extract nutrients and defend against invaders – an important step in preventing pathogens from contaminating fruits and ...

User comments : 0