NEW STUDY BRINGS WHAT GOES WRONG IN INHERITED ALS INTO FOCUS
Work adds to body of research pointing to astrocytes in ALS.

A flaw in the way the body fine-tunes sensitivity in the nervous system
may account for a good bit of the ability of one sort of ALS to destroy
motor neurons, according to a Belgian research team led by Packard
scientist, Wim Robberecht. The work provides a concrete explanation for
the uncommon but much-studied ALS caused by inheriting the gene for a
mutant form of a common enzyme called SOD1.

The study, done with lab rats, should help researchers seeking therapy
for the inherited disease. But the work is also important in
understanding the more typical "sporadic" ALS because of implications
for pathways likely held in common for both forms of the disease.

The report appears in this month's Proceedings of the National Academy
of Sciences.

An added benefit: It also offers a plausible idea why ALS targets only
motor neurons, out of all the nerve cells in the nervous system.

The research centers on receptors on motor nerve cells * neurons *
that respond to the nerve transmitter glutamate. When glutamate
receptors are stimulated, the neurons that house them fire, tripping
normal message-carrying activity. Should the receptors become
overstimulated, however*as happens in stroke, epilepsy and ALS *
neurons die.

Death by overstimulation appears to hinge on the actual structure of
the receptor. And a body of work by Robberecht and colleagues shows that
structure isn't fixed but can vary. Part of the new study shows, for
example, that two different varieties of rats, Holtzman and Wistar,
differ greatly in receptor structure. "This ability to vary is likely
one way the body fine-tunes the nervous system to make it more or less
responsive to the environment," Robberecht says.

In ALS, however, the fine-tuning apparently goes awry, he says, and
motor neurons then become dangerously sensitive to stimulation, in
effect, firing themselves to death. And what fine-tunes the receptors?
Robberecht's group showed that neighboring cells called astrocytes hold
those reins, in ways that aren't yet clear.

"Some sort of protein secreted by astrocytes ultimately affects the
structure of the glutamate receptors," Robberecht says. Evidence comes
from finding that the culture liquid surrounding astrocytes grown from
Holtzman rats can protect Wistar rat motor neurons from toxic
overstimulation. Other tests with whole pieces of astrocytes showed the
same thing.

In trying to clarify the fine-tuning process, the scientists analyzed
receptors from both types of rats. A higher proportion of glutamate
receptors from Holtzman rats had a key building block, called the GluR2
subunit. Those rats resisted overstimulation. Wistar rats, however, with
fewer GluR2s, were more likely to succumb.

The GluR2 unit is key because something in its structure lets neurons
resist the inward rush of calcium ions into neurons, an event typical in
disease. High calcium influx is the immediate "trigger" that
overstimulates neurons, leading to death.

"More specifically, then, we believe that astrocytes secrete a protein
that makes motor neurons express GluR2 to a higher degree," says
Robberecht.

So where does ALS come in? The researchers found that in rats with
flawed SOD1, there's a roadblock in the astrocyte-glutamate receptor
pathway. In rats with the mutant SOD1 gene * the one that causes some
inherited ALS in humans * carrying the resulting mutant protein in
their astrocytes abolishes the animals' ability to avoid
overstimulation. "It does that," he says, "by blocking their ability to
add the protective GluR2 subunit to glutamate receptors."

Motor neurons of both Holtzman and Wistar rats died when their
astrocytes carried mutant SOD1.

The find suggests new approaches to therapy. "Putting healthy
astrocytes around motor neurons may reduce their vulnerability," says
Robberecht. "It may be easier to correct the environment in the spinal
cord by providing such cells than by replacing motor neurons themselves.


"We also found it interesting," he adds, "that of all the neurons in
the body, motor neurons * healthy ones, we're talking about now *
have the fewest GluR2 subunits. This could make them naturally
vulnerable to neurodegenerative disease."


In addition to being a Packard grantee, Robberecht is also one of the
Center's scientific advisors.

==========================

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 collaboration of scientists worldwide, working
aggressively to develop new treatments 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 from the laboratory bench to the
clinic in record time.

Scientists and clinician members of the Packard Center are unsurpassed
at moving drugs reliably and rapidly from preclinical experiments to
human trials. They're linked, directly or indirectly, to the world's
major pharmaceutical and biotechnology companies, which have both
infrastructure and experience to make promising drugs into therapies.

Packard Center 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 devastating, progressive 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.

For more information about The Robert Packard Center for ALS Research
at Johns Hopkins, including information on its latest research and
treatment, visit www.alscenter.org

==========================
_________________________________________
Rebecca Berger
Administrative 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
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