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http://www.alscenter.org/news/briefs/070809.cfm


NEW ALS PROTEIN COULD BE A KEYSTONE
Molecule is identical in patients with the most common ALS and the
inherited form

Ever since scientists created an animal model of ALS some 15 years ago
* one based on rodents engineered to carry copies of a flawed human
gene for a rarer familial form of the disease - they've worried that the
widely-used model doesn't well enough reflect the most common form of
ALS.

Even though, in humans, the familial and sporadic forms of the disease
are virtually identical symptom-wise, researchers had concerns that at
the most basic level, the animal model differed enough between the two
to slow progress on therapy for all ALS.

But now, a new study by a team of Packard Center investigators and
their colleagues at several U.S. research institutions, used forefront
techniques to show that both familial and sporadic ALS produce an
identical complex of flawed protein - one never seen before - in the
spinal cord. The protein appears unique to ALS, and tissue samples from
healthy people or from other neurodegenerative diseases - Huntington's,
Parkinson's and Alzheimer's - don't show it.

"We had assumed that at some point, fALS and sALS had to have some
downhill pathway in common in the nervous system," says Packard director
and researcher Jeffrey Rothstein, "but evidence for that has been
elusive until now.

"Finding what looks like a common underlying pathology, though, makes
our studies with the animal models relevant for both forms of ALS,"
Rothstein adds, "and it means we can still push ahead with the therapies
we're planning to test."

The study appeared in the July issue of the Proceedings of the National
Academy of Sciences.

Both old and new studies center on the molecule, superoxide dismutase
or SOD1, an enzyme in plentiful supply in the body. A mutation in the
gene coding for SOD1, found in patients with a family-based form of ALS,
causes their disease. Some 110 different mutations of SOD1 exist -
Packard scientists and others have shown - each making a slightly
different, misfolded protein capable of bringing on the disease, though
no one knows exactly how.

No mutations have appeared, however, in the SOD1 that the 90 percent of
patients with sporadic ALS produce.

But because existing techniques for revealing misfolded proteins aren't
particularly sensitive, scientists have never been totally sure that
oddly-shaped SOD1 isn't found in tiny quantities in patients with the
more common disease.

Now, in the present study, researchers employed a new, ultra-sensitive
way to try to rule that out. The technique takes advantage of the fact
that different folded proteins respond differently to a specific binding
agent. Such tagging makes the molecule more obvious.

The result, from spinal cord tissue samples from autopsied patients,
was that an altered form of SOD1 was present in patients with sporadic
ALS. Also telling is that the same form was found in the smaller
percentage of familial ALS patients who don't have the SOD1 mutation.

"Does this altered SOD1 somehow help cause sporadic ALS? Could it in
some way accelerate disease?" Rothstein asks. "This study doesn't answer
that. Only future experiments will tell. But these findings are
intriguing," he says, "and certainly bear investigating."

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Don W. Cleveland, of the Ludwig Institute for Cancer Research at the
University of California, San Diego, and Jeffrey D. Rothstein, with the
Johns Hopkins Medical Institutions were the Packard members of the team.
Other authors were with the California Pacific Medical Center Research
Institute, San Francisco and the University of Pittsburgh School of
Medicine.


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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.