At least five major chemical pathways in nervous system cells go awry
in ALS, researchers have noted in the last decade. Now a new study led
by a Packard Center researcher points to yet another one. But this
pathway may be relatively easy to put right, parts of the study suggest,
and, as a new area directly on the route leading to motor cell death, it
offers an attractive target for therapies.

The study, which uses mouse models of ALS, appears in the March 15
Journal of Neuroscience. It was funded by The Robert Packard Center for
ALS Research at Johns Hopkins and by the Canadian Institutes of Health
Research.

The work centers on a family of molecules called Cdks (for
cyclin-dependent kinases), which normally either help signal cells to
divide or help regulate nervous system development. Cdks are active in
growing animals. They get shut off in cells that no longer undergo
mitosis, like motor neuron cells. "Problems may arise if Cdks become
active in cells where they're meant to be quiescent," says McGill
University biochemist Jean-Pierre Julien, Ph.D., who oversaw the
research team.

"We know that if you abnormally activate them in cultures of nerve
cells, those cells die pretty handily," he says. "Now we've gone on to
show that in animal models of ALS, whose nerve cells also die, those
same Cdk molecules are also abnormally active."

Julien's team studied SOD1 mice, a standard animal model of the
disease. These animals carry copies of a human gene that sparks a rare
genetic form of ALS. Like humans, SOD1 mice undergo progressing muscle
weakness and death.

By using sensitive tracers, the researchers showed levels of most Cdks
were significantly higher in SOD1 mice than in healthy ones.

Two of the Cdks are especially crucial, Julien says, because, activated
abnormally, they apparently trip cell suicide programs that quickly
bring about cell death.

What starts it all? Scientists know cell stress; inflammation and
abnormal cell chemistry in general can raise Cdks in cells. Julien
speculates something similar, like inflammation, may spark the Cdk
upswing in the mice.

Interestingly, he says mice given the drug minocycline, an antibiotic
that reduces inflammation, experience less Cdk uproar in their cells.
"Inhibitors of Cdks, which we already know are protective in other
neurodegenerative conditions," Julien adds, "might give us a reasonable
avenue to explore for ALS treatment." In fact, other Packard-funded
scientists are now exploring CDK inhibition as future therapy for ALS.

Other scientists in the study were Minh Dang Nguyen, Mathiew Boudreau,
Jasna Kriz, Sébastien Couillard-Després, Holger Patzke, Michael
Ahlijanian and David Kaplan.

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About The Robert Packard Center for ALS Research

Located in Baltimore, the Robert Packard Center for ALS Research at
Johns Hopkins University is a collaboration of scientists worldwide
working aggressively and rapidly to develop new treatments and find a
cure for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's
disease. It is the only institution of its kind dedicated solely to the
disease. Research conducted by the Center is meant to translate from
the laboratory bench to the clinic in record time. Scientists and
clinician members of the Center are unsurpassed at moving drugs reliably
and rapidly from pre-clinical experiments to human trials.

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 Robert Packard Center for ALS Research at Johns
Hopkins, including the latest information on ALS research and treatment,
log on to www.alscenter.org.