'New and Important Player' Advances Understanding of ALS

by Amy Madsen on Fri, 2010-12-03 13:09

Researchers have identified developmental abnormalities in immature 'NG2+' nervous system cells in ALS-affected mice that appear to play a role in the ALS disease process  

Article Highlights:
  • An MDA-supported study team has found that "NG2+" stem cells, which mature into a particular type of central nervous system support cell called oligodendrocytes, exhibit a developmental process in mice with a form of ALS that is dramatically different from the process observed in unaffected mice.
  • Although study results showed that NG2+ cells didn't deviate from a developmental pathway that led them to mature into oligodendrocytes, the cells' maturation in unaffected mice progressed steadily and methodically, while in the ALS-affected mice, the NG2+ cells divided into far greater than normal quantities of oligodendrocytes, which developed abnormally and died early.
  • The MDA-supported study team speculated that the developmental abnormalities of NG2+ cells in ALS-affected mice could be a causative factor in the ALS disease process, or could instead reflect the body’s attempts to compensate for ALS-mediated degeneration.
  • These findings implicate oligodendrocytes as "a new and important player" in ALS, the authors wrote.

A population of stem cells called NG2+ cells — which mature into central nervous system support cells called oligodendrocytes — exhibit significant developmental differences in healthy mice compared to mice with a disease resembling human ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).

"Our preliminary studies suggest that these cells very powerfully affect disease onset in our animal models," said Jeffrey Rothstein, a professor of neurology at Johns Hopkins University in Baltimore and director of the MDA/ALS center at that institution.

"These cells contribute in a very large way to metabolic survival of the motor neurons, and in as-yet-unpublished studies, we've shown this process is severely disturbed in ALS." Motor neurons are muscle-controlling nerve cells in the brain and spinal cord that are lost in ALS.

The research group published its findings in the Nov. 18, 2010, issue of the journal Neuron. MDA supported Rothstein for this work.

About NG2+ cells

NG2+ cells have been a subject of debate among researchers. Previous studies suggested that the immature cells can be coaxed (in isolated cultures in the laboratory) into becoming various types of important central nervous system (CNS) support cells, such as astrocytes (which provide numerous supportive functions including providing nutrients to nervous system tissues and helping repair injured brain and spinal tissue), and oligodendrocytes, which insulate the fibers that carry signals to and from nerve cells in the brain and spinal cord. They do this by coating the fibers with a substance called myelin.

However, this study confirmed that — outside of a laboratory — the NG2+ cells turn into only one type of support cell: oligodendrocytes.

About the findings

The investigators tagged NG2+ cells in both healthy and ALS-affected mice, enabling them to track the cells' development over time.

They found that in healthy mice the NG2+ cells experience a period of rapid growth and expansion shortly after birth, settling afterwards into a steady pattern of dividing — sometimes into oligodendrocytes, and other times into new NG2+ cells able to continue a steady turnover.

This constant turnover of oligodendrocytes throughout life may be necessary to maintain myelin, the researchers wrote.

But the fate of NG2+ cells is dramatically different in mice with ALS caused by a mutated SOD1 gene, the study showed. (Mutated SOD1 protein is associated with inherited ALS, but may play a role in other forms of ALS as well.)

In the spinal cords of ALS-affected mice, the NG2+ cells grew and spread at a far greater speed than they did in normal mice, after which they developed into abnormal oligodendrocytes and then quickly died.

In addition, the ALS-affected mice produced significantly greater numbers of oligodendrocytes than they did other types of central nervous system cells, and produced far more of them than are produced in unaffected mice.

This observation, the researchers wrote, suggests that significant oligodendrocyte death or injury occurs before other forms of neurodegeneration begin in ALS.

Also of note: The abnormal oligodendrocyte-generating activity in ALS mice occurs in the same place where motor neurons die.

It remains unclear whether the change in behavior of these NG2+ cells is meant to be a protective response in reaction to the degeneration associated with ALS, or if it accelerates the death of motor neurons in the disease.

Next steps

Although the investigators saw no evidence that NG2+ cells become anything other than oligodendrocytes in both healthy and ALS-affected mice, the question remains whether it may be possible to manipulate factors restricting the cells' development. This might allow scientists to coax the NG2+ cells to develop into other CNS cell types, such as astrocytes, that can go on to replace cells that have died as a result of injury or disease.

"The next steps are to understand the specific factors that turn NG2+ cells into oligodendrocytes," Rothstein said, "and to determine whether removal of the mutant SOD1 protein from the NG2+ cells can change the outcome.”

Rothstein added that additional research is needed to determine if and how oligodendrocytes contribute to the ALS disease process; to develop imaging markers able to indicate oligodendrocyte pathway injury in ALS; and to search for biochemical targets in the pathway at which to aim therapeutics. 

Meaning for people with ALS

The differences in the fate of NG2+ cells in healthy mice and those with SOD1-mediated ALS point to oligodendrocytes as a possibly "new and important player" in the progression of ALS, the investigators wrote.

"The biggest change in understanding and continuing research into ALS is the potential implication that oligodendrocytes are involved in the disease process," Rothstein said.

Increased understanding of the ALS disease process is crucial to determining the ways in which scientists might thwart it.

Further examination of the developmental differences and their consequences among NG2+ cells in normal mice and mice with ALS will provide investigators with valuable information necessary to determine the disease's molecular underpinnings and design therapies to combat them.

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