IN ALS, IT'S NOT THE NUMBER OF AILING ASTROCYTES THAT COUNTS

The spinal cord after an auto accident or some other physical trauma
could best be described as being in a biological uproar. A wide variety
of cells disappear. The chemical environment changes. And of interest to
Packard researchers is the sharp upturn in the number of astrocytes. The
star-shaped cells that are motor neurons' companions quickly become far
more common - often within 24 hours of injury.

This jump is likely protective, studies show; if you block the
astrocyte response in lab rats after a trauma, for example, injury is
much greater.

"But in ALS, important differences exist," says Packard scientist
Nicholas Maragakis. Certainly, as in trauma, astrocytes increase in both
animal models of the disease and in the humans who have it. The numbers
in both are comparable.

But somehow, any neuroprotection that astrocytes offer after a cut or a
blow isn't apparent in ALS. "We really understand very little about how
these cells behave before or after symptoms appear, Maragakis explains,
"and what's behind it."

So he and colleagues aim to change that.

A decade of research, much of it in Packard labs, shows that more than
numbers of astrocytes increase in injury or disease. The cells
themselves balloon out and their internal chemistry changes as different
genes switch on or off.

And a host of recent studies in animal models of ALS points to a role
for ailing astrocytes in motor neuron death. Astrocytic molecules that
clear toxins from the motor neuron environment, for example, are in
short supply. And clumps of abnormal protein clutter astrocytes'
cytoplasm. "By the time ALS symptoms appear," Maragakis explains,
"astrocytes are clearly far from normal and become more so as the
disease continues." They may not start ALS, but the diseased cells
certainly have a hand in its progress.

The approach Maragakis and other Packard scientists are taking is
thorough: to try to block the major astocytic changes in good animal
models and see if that either halts or slows ALS.

In the first of these studies, just reported in the journal
Experimental Neurology, he blocked mature astrocytes from dividing. His
team used two animal models of ALS, one, the classic SOD1 mouse model
that contains a flawed gene for familial ALS. The other: mice whose
central nervous system has been attacked by Sindbis virus. Both types
typically have a significantly higher astrocyte count than healthy
animals.

The result was useful, though not glamorous. The already high astrocyte
number didn't increase. "That suggests that most of them come from a
different source - stem cells," says Maragakis. (New research from his
lab has confirmed this alternate stem cell source. Now it appears to be
the key one.)

And of more interest, survival of the lab animals' motor neurons or
survival of the animals themselves didn't change. "What this tells us,"
he explains, "is that whatever astrocytes do to advance ALS most likely
has to do with which genes are active or in how they affect the spinal
cord environment. It's not the actual number of dividing astrocytes
that's so important."

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About The Robert Packard Center for ALS Research at Johns Hopkins
www.alscenter.org

Located in Baltimore, the Robert Packard Center for ALS Research at
Johns Hopkins is a worldwide collaboration of scientists aimed at
developing therapies and a cure for amyotrophic lateral sclerosis (ALS),
also known as Lou Gehrig’s disease.

The Center is the only institution of its kind dedicated solely to the
disease. Its research is meant to translate rapidly from the lab bench
to the clinic, largely by eliminating time spent waiting for grants and
lowering institutional barriers to sharing scientific results.

Scientists and clinician members of the Packard Center have moved drugs
reliably and rapidly from preclinical experiments to human trials.
Direct or indirect links to international biotech or pharmaceutical
companies bring the infrastructure and experience needed to make
promising drugs into therapies.

Packard scientists are the first to propose and test a combination
approach to drug therapy, a tactic that has worked for AIDS, cancer and
other diseases.

ALS is a progressive, disabling neuromuscular disease that causes
complete paralysis and loss of function - including the ability to
eat, speak and breathe. ALS progresses quickly and is not curable. Most
patients die within five years of diagnosis.


_________________________________________
Rebecca Berger
Research Program Coordinator
Robert Packard Center for ALS Research at Johns Hopkins
5801 Smith Avenue | McAuley Suite 110
Baltimore, MD 21209
410.735.7678 direct
410.735.7680 fax
rberger6@jhmi.edu
www.alscenter.org