Subject: Robert Packard Center ALS News Network

View this article online at:
http://www.alscenter.org/news/briefs/080903.cfm

NEW STUDY ADDS AN INTRIGUING BIT TO ALS/MITOCHONDRIA PUZZLE

In ALS, trouble is afoot in mitochondria. And while nobody knows why,
precisely, new research is showing how seemingly slight disruptions in
their normal interactions with the rest of the cell could have great
consequences.

"Is this the key to understanding the process of ALS?" asks Packard
grantee Giovanni Manfredi. "We don't know." But given the importance of
mitochondria – the organelles that are the body's major energy source
– his research follows a promising avenue for learning about the
disease and finding targets for its therapy.

It also shines light on how mitochondria interact with other cell
systems – a complex and little-studied give-and-take that may be
involved in a number of diseases.

A report on the work appeared in this month's online Journal of
Biological Chemistry. Manfredi is a neuroscientist with the Weill
Medical College of Cornell University.

For several years, Manfredi and others have known that ALS's symptoms
begin in both model mice and humans at the same time that mitochondria
become misshapen and start to fall apart. Both the animal models and
people with the most common familial type of ALS carry a mutated form of
the SOD1 (superoxide dismutase) gene that causes their disease.

Logically, then, Manfredi's team has been trying to piece together the
SOD1-sick mitochondria connection. It's part of a major effort by ALS
researchers to see, overall, how SOD1 can cause the disease.

Normal SOD1, a molecule manufactured in the cell's cytoplasm, is able
to slip through both of the outer and inner membranes that characterize
mitochondria. Once inside, it performs a useful service, clearing away
toxic charged molecules – free radicals – that build up. Other
proteins are "imported" into mitochondria as well, coming in to do
various tasks.

Not every molecule can enter, however – only those shaped so they're
compatible with mitochondrial systems that pull them in like so many
flounder on a fisherman's deck.

In this recent research, Manfredi has focused on an enzyme protein
called KARS, one normally given easy entry. Inside mitochondria, KARS
plays a quiet but necessary part in the manufacture of specific
molecules tailored to their use.

What Manfredi discovered was that mutant SOD1, but not healthy (wild
type) SOD1 interacts physically with KARS, causing an abnormal
structural change that prevents or disrupts KARS' being imported into
mitochondria. "This all happens on the mitochondrial surface," Manfredi
explains. "KARS, in essence is abducted by mutant SOD1, resulting in its
misfolding."

Not only does this prevent KARS from doing its useful role but also,
Manfredi speculates, clumps of misfolded KARS and mutant SOD1 may so gum
the surface of mitochondria that other necessary proteins are kept from
their normal transport in.

Further, says Manfredi, warped KARS is likely to be recognized as "bad"
by the cell's housekeeping machinery, placing a strain on that system as
well. And neurons, he says, are likely to be more sensitive to these
changes than other cells. In the mouse models, for example, non-nervous
system tissues looked undamaged.

"So we see that a mitochondrial problem can cause ongoing difficulties
elsewhere in the cell," says Manfredi. "Our work adds to the suggestion
that there's a system of protein import in mitochondria whose
malfunction could be involved in disease such as ALS*. The idea is an
intriguing one."

* Studies elsewhere show that abnormalities in another
mitochondrial-entering protein similar to KARS is responsible for the
neurodegenerative Charcot-Marie-Tooth disease, a hereditary illness that
affects sensation and movement in the lower legs, mostly.

___________________________________

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 worldwide collaboration of scientists aimed at
developing therapies 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 rapidly from the lab bench
to the clinic, largely by eliminating time spent waiting for grants and
lowering institutional barriers to sharing scientific results.

Scientists and clinician members of the Packard Center have moved drugs
reliably and rapidly from preclinical experiments to human trials.
Direct or indirect links to international biotech or pharmaceutical
companies bring the infrastructure and experience needed to make
promising drugs into therapies.

Packard 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 progressive, disabling 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.


_________________________________________
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

_________________________________________
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
www.fiesta5K.org