From: alscenter@jhmi.edu

To: The ALS Community

Date: July 2, 2007

Subject: Robert Packard Center ALS News Network


View this article online at:
http://www.alscenter.org/news/briefs/070629.cfm

MUSCLES MORE THAN PASSIVE VICTIMS IN ALS, STUDY SUGGESTS

Work offers a new line of therapy research to slow ALS

Scientists trying to understand the workings of ALS haven't thought
much about what part, if any, that muscles play. Their view on what
transpires in triceps and quads is that they're more the disease's
victims than major players.

There's some science behind that opinion. A recent study by Packard
researcher Don Cleveland showed that if the muscles of model mice - and
only the muscles - held active genes for inherited human ALS, the mice
stayed healthy. That would seem to nix muscles as a source of ALS.

New work by Packard scientist Jeffrey Johnson, however, suggests that
we shouldn't be quick to dismiss muscles. It also offers a new
therapeutic path that he's actively investigating - one that works by
boosting natural efforts to stave off ALS's worst effects.

In his several years as a Packard grantee, Johnson's work has dealt
with one of the body's built-in detox systems. Cells rely on the
so-called phase II detoxification enzymes - the same system that
broccoli chemicals stimulate - to blunt the flood of damaging free
radicals that occurs in many illnesses, including ALS. More
specifically, Johnson has focused on what activates that system, what
turns on the battery of genes coding for its enzymes.

A body of research, including Johnson's, shows that the on switch for
phase II involves a specific protein and chemical cascade, dubbed the
Nrf2-ARE pathway. And the studies go one step more to show that when the
ARE complex is in place and active, whether in cultures or in live
animal models exposed to toxic situations, nerve cells get significant
protection from damage. In addition, other pathways important to cells'
general working are strengthened. "So," says Johnson, "this system bears
investigating for ALS."

Recently, he followed activation of the Nrf2-ARE path in two different
animal models of ALS.

A method for visually tracking the process let his team see exactly
where this took place and also let him mark the time when cells turned
the Nrf2-ARE system on. "The main point," he says, "is that pathway
activation seems to be a very early indicator of stress, and it appears
in the muscles very early in the disease process, even before symptoms
begin.*"

"What we*re speculating, then, is that, in ALS, the Nrf2-ARE response
in muscles is due to something subtle going wrong at the level of the
synapse between the motor neuron and the muscle," Johnson says.

Of special interest therapy-wise, he adds, is that the response varies
within muscles, depending on the type of muscle fiber. Skeletal muscles
affected by ALS contain a mix of "slow twitch" or type I fibers that
allow sustained aerobic activity and "fast" type II fibers that exhibit
greater force but that fatigue more quickly.

Johnson's team found that the Nrf-2-ARE system is activated only in
type I fibers. He thinks it's no coincidence that the usual activity
between motor nerves and the type I muscle lasts longer - resists
paralysis longer - than in type II.

And it's extremely interesting that the pattern of activation follows a
path from type I muscle fibers to nerve cells to key parts of the spinal
cord that mimics human ALS.

"Of course it's speculative at this stage, but if we could activate the
system in type II fibers, that might stave off the worst symptoms longer
and affect ALS progression," he explains. Johnson's working to that end.
He's now testing an ALS mouse model in which those very fibers have been
engineered to turn on the dormant protection within.

The work was jointly funded by The Robert Packard Center for ALS
Research at Johns Hopkins and the ALS Association.

----------------------------------------------------

This study will appear in the journal, Experimental Neurology and can
be accessed currently as an Article in Press through the following link:
http://dx.doi.org/10.1016/j.expneurol.2007.05.026


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