Article available online at:
http://www.alscenter.org/news/briefs/080410.cfm

TELL-TALE PROTEIN CLUMPING IN ALS IS LESS COMPLEX THAN EXPECTED
That could be a good thing for potential therapies, researchers say

More than a decade ago, when scientists uncovered a mutant gene for one
type of heritable ALS and saw that its resulting protein, called
superoxide dismutase (SOD1) was also flawed, they beheld their first
clue to the cause of the vile disease.

More exciting, even, was the possibility * because of similarities in
all forms of ALS * that the find would ultimately lead to therapy.

Today, while cell and animal models of ALS engineered with the mutant
human SOD1 gene have vastly advanced knowledge, the answers on how
flawed SOD1 contributes to motor neurons' downfall lie just out of
reach.

This March, however, a U.S. research team including Packard Center
biochemist/neuroscientist David Borchelt brought the truth of the
SOD1-ALS connection closer.

In two studies reported in the Journal of Biochemistry, the scientists
performed the first in-depth analysis of abnormal, microscopic clumps of
mutant SOD1 protein that form in motor neurons. They also clarified
cell mechanisms that produce them.

Protein aggregates are a hallmark of Parkinson's and Alzheimer's and
other neurodegenerative diseases. Though the makeup and timing of the
deposits varies according to disease, the fact that they're toxic seems
certain. In ALS, aggregates appear both in animal models and in humans
with the disorder. And earlier animal model work in Borchelt's lab has
shown that clumped mutant SOD1 appears with the onset of disease
symptoms.

Until now, however, no one had closely analyzed the aggregates.
Knowing their makeup could provide clues to the process that made them
and, ultimately, perhaps, explain why they're toxic.

In one study, Borchelt and a scientific team at UCLA, led by Julian
Whitelegge and Joan Valentine, extracted aggregated SOD1 from spinal
cords of three different varieties of mutant SOD1 mice, all of which
were models for ALS.

Using a variety of biochemical techniques, including mass spectroscopy
and sophisticated chromatography, they showed mutant SOD1 to be the only
protein found consistently in the clumps. "This suggests that
aggregating comes naturally to abnormal SOD1 molecules," Borchelt says;
"by itself, then, mutant SOD1 could be responsible for the masses we see
in cells." The clumping might be part of cell attempts to compact the
protein so its toxic portions are hidden.

"We won't know what the clumps do, though, until we find how to keep
them from forming," he adds.

To that end, the scientists are investigating what triggers aggregates.
Earlier work hinted that oxidative stress * the sort of insult that a
number of environmental events can deliver * might have a role in
making mutant SOD1 "sticky." But this new research says that's unlikely,
that something intrinsic in the molecule is at work.

"These studies will help us identify the events crucial to generating
substances toxic to cells in ALS," says Borchelt, "while they'll also
reveal chemical targets most likely to respond to therapy."

Packard scientist Borchelt heads the McKnight Brain Institute at the
University of Florida, Gainsville.

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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 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

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_________________________________________
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
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