WHY THE NEW GENE FINDINGS ARE A CALL TO ACTION - A PACKARD PERSPECTIVE
http://www.alscenter.org/news/briefs/090304.cfm

In 2003, when New England ALS scientists announced they'd discovered
another form of familial ALS - the sixth one, and an adult form that
seems to strike harder in the lower extremities and have a somewhat
faster course - the hope was that the gene for it would soon surface.

High excitement in the ALS research community always accompanies
finding a new gene: Perhaps this one holds clues to reveal what triggers
motor neuron death; perhaps this one will spark a really effective
therapy.

Last week, after a six-year search, the gene was announced by seasoned
collaborators at the University of Massachusetts and Massachusetts
General Hospital. Another research team at King's College in London
backed up the finding. Found where they'd suspected it, on chromosome
16, the mutated FUS gene (for "fused in sarcoma") is responsible for
perhaps 5 percent of familial ALS. And pinpointing it, after a long,
thorough search, would be news enough.

But this discovery appears to go beyond the usual. Packard scientists
warmly welcome the appearance of m(for mutated) FUS for a key reason: It
lends clout to a theory about a major destructive process in ALS that's
been gathering evidence at the Packard Center and elsewhere more than a
decade.

"The fascinating thing about having the FUS gene linked to ALS," says
Packard Scientific Director Piera Pasinelli, "is that it's yet another
gene that plays a part in RNA processing."

And having successful functioning of that molecule is crucial for cells
to work normally. By way of background: RNA - specifically the messenger
RNA molecule - carries DNA's blueprint for assembling proteins into the
cell cytoplasm where their actual assembly occurs. Yet getting RNA to
reflect DNA's "message" accurately, modifying it for efficiency and then
transporting it from the cell nucleus to the cytoplasm is an involved,
multi-step process. And it's a one that can go awry.

In 1998, Packard scientists first published the find that some 65
percent ALS patients harbor abnormal messenger RNA molecules,
specifically in the injured parts of their central nervous systems. But
no one has known the cause of that or what, if any, part it plays in
ALS's downhill course.

More evidence: Not long ago, Packard researchers helped discover the
familial ALS4 gene, one for an abnormal form of a protein called
senataxin. Like FUS, the senataxin gene also has an RNA role, overseeing
proper production of messenger RNA from its DNA blueprint.

And last year, the King's College group showed mutations in yet another
gene - one called TDP-43 - that appears both in patients with a variety
of different familial ALS types and, amazingly, in sporadic ALS patients
as well. Healthy people lack these mutations. (Last week, Packard
scientist Wim Robberecht and his European team added to that,
discovering a new variation of the TDP-gene in familial ALS patients.)
*

Among TDP-43's list of accomplishments? RNA processing.

All this suggests that flawed RNA metabolism, then, may join ALS's
seven "ugly stepsisters," as another of the biological pathways to go
wrong in ALS. (In scientific terms, the seven stepsisters are: oxidative
damage, misfolded protein aggregates, dysfunctional mitochondria,
defects in motor neuron transport, growth factor deficiency, pathology
of glial cells, glutamate excitotoxicity.)

What has Packard scientists most engaged, however, is where the flawed
RNA metabolism could lead. It's interesting, for example, that both
patients with ALS from mTDP-43 and those with ALS from mFUS appear to
show clumps of misfolded proteins - protein aggregates - in central
nervous system cells, early in the disease. "This suggests that these
aggregates are key agents, that they participate early in the genesis of
ALS," says Packard scientist Phil Wong, who has just made a mouse model
of ALS using a mutant TDP-43 gene.

So an important next step, both for understanding and for therapy, Wong
says, is to "see whether these aggregates are indeed critical players or
if, instead, they're just ‘tombstones' that mark dying motor neurons."
His mouse model should help answer that question.

In this, the new "stepsister" may be the most useful. Because it shows
up in both familial and sporadic patients, some researchers are even
speculating that RNA gone awry may be the missing overarching principle
that tells how the stepsisters are related. In other words, some are
hoping it may be the key process that causes ALS.

"The new discoveries, we believe, point strongly to flawed RNA
metabolism as a key disease process to imitate in animal models for
ALS," says Rothstein.

"It's these tools - the gene-primed model mice and fish and fruit flies
that Packard scientists offer the world's research community - that will
enable us to understand ALS. Ultimately, they'll become the agents we'll
all use to find effective therapies."

*Robberecht is already busy making a zebrafish model of ALS using
mutant TDP-43. His Packard colleague J. Paul Taylor, has begun testing a
new TDP-43 fruit fly model.


___________________________________

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
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