In amyotrophic lateral sclerosis, neighborhood may be
everything, if a new study in mouse models of the disease
holds true for patients.
ALS, or Lou Gehrig's disease, brings about a gradual
death of the motor neurons that activate muscles. Paralysis
follows. But according to work described Oct. 3 in the
journal Science, the cells that are next to motor
neurons — but aren't themselves nerve cells —
can play a major role in advancing or limiting the
"What we've been given is a new principle for
extending survival or, perhaps, overcoming ALS, based on
how many healthy cells surround an ailing motor nerve
cell," said Don Cleveland, a scientist with the
Packard Center for ALS
Research at Johns Hopkins and, with Larry Goldstein,
co-leader of the research team.
"All this has great implications for stem cell
therapy," he said. "We now believe delivery of normal,
non-neuronal cells to spinal cords could be completely
protective, even without replacement of a single motor
In a series of experiments, the team measured the
effect of having different proportions of healthy cells to
at-risk cells in mice, clocking their survival time.
Normally, the scientists work with standard animal models
of ALS. Those mice or rats carry a mutant human gene
— called SOD1 — that triggers a rare, inherited
form of the disease in people. In these models, every cell
carries a mutant SOD1 gene. The animals typically slip into
death by the time they're 6 to 8 months of age.
But in this study, the researchers used chimeric
animals — mice engineered to be a mix of normal
cells, also called wild type, and cells containing the
mutant SOD1 gene. They tagged the cells with molecular
flags to make it clear which were which. The percent of
wild-type cells in the animals' spinal cords ranged from 5
percent to 90 percent.
Having wild-type cells mixed in had the effect of
extending mouse survival from one to eight months,
depending on the number of cells and type of SOD1 mutation.
In a second group of chimeric mice, brought about by a
different technique and with a different type of tracer,
the animals survived disease-free until sacrificed for
study at an age at least twice the age at which typical
SOD1 animal models die.
Even though further study showed that as high as
three-fourths of the motor neurons in the animals' spinal
cords carried the mutant gene, all the motor neurons
remained amazingly healthy, apparently from having healthy
non-neuronal cells in the neighborhood. This was especially
true of the second batch of mice, which had no microscopic
evidence of disease.
"It's really striking," says Cleveland, "to see what a
small number of normal cells effectively eliminated damage
to motor neurons from the ALS-causing genetic error."
The opposite effect also appeared: Mice with normal
motor neurons but with surrounding cells carrying an SOD1
mutation showed early signs of disease. Normal neurons,
then, can apparently acquire something toxic from at-risk
non-neuronal neighboring cells.
"So we're seeing a real-life metaphor here," Cleveland
said. "Living in a bad environment can damage good cells.
And more important, restoring a better environment to 'bad'
neurons by surrounding them with healthy neighbors can
significantly lessen toxic effects. In some cases, having
normal cells completely stops motor neuron death."
Research conducted by center scientist and team member
Jean-Pierre Julien at Laval University in Quebec was a key
contribution to the results. Researchers Cleveland and
Goldstein are both at the University of California, San
Diego, where Cleveland heads the Laboratory of Cell Biology
at the Ludwig Institute for Cancer Research.
The research was funded by the Packard Center for ALS
Research at Johns Hopkins, Project ALS, the ALS
Association, the U.S. National Institutes of Health, the
Canadian Institutes of Health Research, the Angel Fund for
ALS Research and the U.S. Veterans Administration.
Headquartered in Baltimore, the Robert Packard Center
for ALS Research at Johns Hopkins is a collaboration of
scientists worldwide who are working aggressively to
develop new treatments and a cure for amyotrophic lateral
sclerosis. The center is the only institution of its kind
dedicated solely to the disease. Its research is meant to
translate from the laboratory bench to the clinic in record