A scientist new to The Packard Center for ALS Research has shown that
key reactions in mitochondria, the small bodies within cells that supply
energy to cells, are disrupted just before cells begin to die from the
disease. Work by Giovanni Manfredi ,M.D., Ph.D., and his research team
support the idea that injury to mitochondria is a step leading to the
actual death of motor neurons-the main site of injury in ALS.

Manfredi's work was carried out in mouse ALS models that carry a
mutated human gene coding for a protein called superoxide dismutase 1
(SOD1). People with mutant SOD1 genes develop a specific inherited form
of the disease.

Studies by others have shown that ALS patients--those with either the
inherited or the more common "spontaneous" form---often have
mitochondria that are swollen and/or misshapen. Mitochondria in mouse
models are also clearly in trouble.

The work by the Manfredi team, published recently in the Journal of
Biological Chemistry, showed that, in addition to having an altered
appearance, mitochondria were also impaired in function, in their
chemical reactions that produce energy. This was especially obvious in
the spinal cord, which happens to be the body site most affected in ALS.

The study is the first to show mutated SOD1 leads to a loss of the
normal activity of mitochondria in standard mouse models of ALS.

The changes in the tiny organelles didn't appear before the model mice
were 13 weeks old, about six weeks before their death. This suggests
that mitochondrial changes may not be the event that triggers ALS, but
may be closely related to the actual death of cells.

Confirming results of other Center scientists, Manfredi also found that
both mutant and normal SOD1 appear to collect in small compartments
within mitochondria. But only the mutant form seems to be linked with
problems. "We don't understand how it causes dysfunction," Manfredi
says, "but we're testing the possibilities."

One idea is that mutant SOD1 is somehow "warped" and can't function
properly. Normal SOD1 is an enzyme that destroys a highly reactive
molecule called superoxide, a destructive molecule that's a byproduct of
energy-making in mitochondria. It's possible, the researchers say, that
a shortage of normal SOD1 leaves superoxide free to damage mitochondria.
Manfredi's team, in fact, found evidence of that sort of damage.

Another idea is that mutant SOD1 accumulates in mitochondria,"gumming
up" normal processes. The team, as have other Center researchers, also
found evidence of accumulated mutant SOD1 within and near the outer
membrane of mitochondria.

Whatever the cause of mitochondrial distress, Manfredi says,
understanding its source and the relation to motor neuron damage could
eventually provide targets for needed therapy.

The research team is located at the Weill Medical College of Cornell
University.
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The Center for ALS Research at Johns Hopkins is a collaborative effort
by some of the best ALS and non-ALS scientists to aggressively and
rapidly develop new treatments and find a cure for ALS, also known as
Lou Gehrig's disease. It's the only institution of its kind dedicated
solely to the disease. Research conducted by the Center is meant to
translate from bench to bedside in an expedited time frame. Center
scientists from institutions around the world have made some of the most
important discoveries in ALS, leading to advances in understanding and
treatment of the disease.

The nature of ALS shapes the Center's aggressive, results-oriented
scientific approach. ALS is a devastating, progressive neuromuscular
disease that causes complete paralysis and loss of function -- including
the ability to eat, speak and breathe -- and eventually, death. ALS
progresses quickly and is not curable. Most patients die within five
years of diagnosis.

To learn more about The Center for ALS Research at Johns Hopkins,
including the latest information on ALS research and treatment, log on
to www.alscenter.org.