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A protein linked to increased lifespan in yeast
and worms also can delay the degeneration of ailing
nerve cell branches, according to researchers at Washington
University School of Medicine in St. Louis.
Scientists report in the Aug. 13 issue of Science that
their findings might open the door to new ways to treat
a wide range of neurodegenerative disorders, including
Parkinson’s disease, Alzheimer’s disease,
amyotrophic lateral sclerosis (Lou Gehrig’s disease),
various kinds of neuropathy, and multiple sclerosis.
“It’s becoming clear that nerve cell death
in these disorders is often preceded by the degeneration
and loss of axons, the branches of the cells that carry
signals to the synapse,” says senior investigator
Jeffrey Milbrandt, M.D., professor of medicine and of
pathology and immunology. “If this mechanism for
delaying or preventing axonal degeneration after an
injury proves to be something we can activate via genetic
or pharmaceutical treatments, then we may be able to
use it to delay or inhibit nerve cell death in neurodegenerative
diseases.”
Milbrandt and colleagues Toshiyuki Araki, M.D., Ph.D.,
research assistant professor of pathology and immunology,
and Yo Sasaki, Ph.D., research associate, showed in
mouse nerve cells that the protein SIRT1, which belongs
to a family of proteins known as the Sir2 group, delays
the breakdown of axons in nerve cells mechanically cut
off from the cell body or exposed to a chemotherapeutic
agent.
Scientists previously found evidence that this process
of axonal degeneration may be an active self-destructive
process that the neuron activates under certain conditions.
Increased activation of SIRT1 appears to block some
or all of those self-destructive processes.
Sir2 proteins previously have been linked to extended
lifespans in yeast and the microscopic worm Caenorhabditis
elegans. Scientists are also exploring the possibility
of cancer prevention through drugs that increase the
activation of Sir2 proteins.
Milbrandt’s group was able to identify SIRT1’s
role in axon preservation through study of a mutant
line of mice known for the slowness with which their
nerve branches degenerate after injury. The mice have
a mutation that fuses together parts of two proteins.
One of these proteins, Nmnat1, stimulates the production
of NAD, an essential component in cellular energy production.
The other protein, Ufd2a, is involved in the assembly
of protein tags known as ubiquitins that commonly label
cell proteins for destruction.
“Mutations in proteins that regulate the addition
of ubiquitins have been linked to some forms of Parkinson’s
disease, so we went into these experiments thinking
that the ubiquitin assembly protein portion of the mutant
protein was likely to be behind the protective effect,”
Milbrandt recalls.
However, when researchers studied cultured nerve cells
carrying the mouse line’s mutation, they learned
otherwise. In cells genetically modified to make only
the portion of Ufd2a found in the fused protein, nerve
cell branches degenerated at normal rates when cut or
exposed to a toxin. But branches in nerve cells that
made only Nmnat1 had the protective effect, degenerating
much more slowly under the same conditions.
Additional study showed a mutation that specifically
disabled Nmnat1’s ability to synthesize NAD also
disabled the protective effect. This moved the focus
of their hunt for the cause of the effect from Nmnat1
to NAD.
Efforts to further home in on the protective mechanism
suggested that something affected by NAD in the cell
nucleus was providing the protection.
“We decided to look at Sir2 proteins because they’re
activated by NAD, and once they’ve been activated
they can turn on and off the activity of the genes for
many other proteins,” Milbrandt explains.
The hunch paid off: When they gave nerve cells a dose
of Sirtinol, a drug that shuts down the activity of
Sir2 proteins, the protective effect disappeared. This
was true even though scientists had given extra NAD
to the nerve cells several hours before they were injured,
a step they had previously found could induce the protective
effect.
Through a series of experiments, Araki and Sasaki found
that the protective effect seemed to be most strongly
associated with SIRT1, the first of seven Sir2 group
proteins.
“The next step is to find out what genes SIRT1
is turning on and off that protect axons when the nerve
cell is injured,” Milbrandt says. “We’ll
also be looking at whether gene therapy approaches that
increase these protective effects can delay disease
in mouse models of human neurodegenerative disorders.
We’ve already heard from a number of colleagues
who are eager to give these pathways a try.”
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Araki T, Sasaki Y, Milbrandt J. Increased nuclear NAD
biosynthesis and SIRT1 activation prevent axonal degeneration.
Science, Aug. 13, 2004.
Funding from the National Institute of Neurological
Disorders and Stroke and the Alzheimer’s Disease
Research Center at Washington University.
Washington University School of Medicine’s full-time
and volunteer faculty physicians also are the medical
staff of Barnes-Jewish and St. Louis Children's hospitals.
The School of Medicine is one of the leading medical
research, teaching and patient care institutions in
the nation, currently ranked second in the nation by
U.S. News & World Report. Through its affiliations
with Barnes-Jewish and St. Louis Children's hospitals,
the School of Medicine is linked to BJC HealthCare.
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