From: alscenter@jhmi.edu

To: The ALS Community

Date: April 6, 2007

Subject: Robert Packard Center ALS News Network


View this article online at:
http://www.alscenter.org/news/briefs/070406.cfm

MODEL OF ACCELERATED FAMILIAL ALS SHEDS LIGHT ON DISEASE PROCESS

The devastated offspring from a mating of two types of laboratory mice
- one of them a classic model of ALS, or Lou Gehrig's disease - should
pull scientists' attention more strongly to the mitochondria, cell
structures recently suspected as major players in the death of nerve
cells in that illness.

The animals' rapid decline - they unexpectedly succumbed almost six
times faster than the usual ALS mouse model - suggests their potential
to reveal flaws within mitochondria that can carry out ALS's downhill
course.

While what happens to patients with ALS is well described, the cause of
the disease is not. That's certainly true for its most common, or
sporadic, form. One type of the rarer familial ALS, however - a type
that affects about 20 percent of patients with the disease in their
families - has somewhat clearer beginnings. There, the source of disease
is a mutation in the gene for the common cell protein superoxide
dismutase, or SOD1. But exactly how abnormal SOD1 leads to illness
remains mysterious. And resolving that mystery, scientists say, would
illuminate all forms of the disease.

In a study underwritten by the Packard Center for ALS Research, a team
that includes neuroscientist Jeffrey Elliott at the University of Texas
Southwestern Medical Center in Dallas and Packard neuroscientist
Giovanni Manfredi at Cornell University, found increased amounts of
mutant SOD1 within mitochondria, the cell's chief energy supplier.
Further, they found the higher amounts tied to mitochondrial
destruction. And when mitochondria deteriorate, Manfredi and others
showed earlier - and this study confirm - the animals undergo an
ALS-identical decline.

A description of the work appears in this month's Proceedings of the
National Academy of Sciences.

"These unexpected findings strongly suggest that an early, very toxic
event involves mitochondria in the familial form of ALS," says Packard
Director Jeff Rothstein. "This new observation helps explain the results
of prior studies with diverse protective drugs - such as antioxidants,
anti-glutamate agents, and anti-cell death cascade agents - since they
all have a common element in improving the workings of mitochondria."

This latest research stemmed, basically, from a curiosity to see what
would result if ALS model mice - those carrying human genes for mutant
SOD1 - received an extra supply of a natural molecule that typically
"adjusts" normal SOD1 from an immature to a mature form. Elliott induced
overexpression of the natural CCS molecule in the model mice by breeding
mice engineered to carry human CCS genes with the ALS model mice.

While model ALS mice typically develop symptoms at 180 days and succumb
around 240 days, the dual-gene offspring mice sickened by day 11. Most
survived barely a month. Microscope studies showed rampant
irregularities, specifically in the mitochondria. "It's hard to find a
normal one in these mice," says Elliott. Further study showed that
typical chemical pathways in mitochondria - those for the cell
respiration that produces energy - were also abnormal.

Most interesting, the scientists agree, was the fact that mutant SOD1
inside mitochondria was significantly higher in the dual gene mice than
in normal mice and also higher than in ALS model mice without CCS. "So
CCS is clearly doing something with abnormal SOD1," says Manfredi, "but
we don*t know what."

Because the results are so drastic, adds Elliott, "we think we can use
this as a tool to find out how mutant SOD1 goes on to change the way
mitochondria function." This sort of forcing the hand of disease, he
says, may highlight pathway abnormalities that would otherwise be
difficult to see.

Support for the work came from the Packard Center for ALS Research at
Johns Hopkins, the NIH, the Horace C. Cabe Foundation and other private
sources.

Marjatta Son, Krishna Puttaparthi, Hibiki Kawamata, Bhagya Rajendran
and Philip Boyer were part of the research team.

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

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