Targeting astrocytes slows disease progression in amyotrophic lateral
sclerosis
Science Centric
3 February 2008 | 18:00 GMT
In what the researchers say could be promising news in the quest to
find a therapy to slow the progression of amyotrophic lateral
sclerosis (ALS), or Lou Gehrig's disease, scientists at the
University of California, San Diego (UCSD) School of Medicine have
shown that targeting neuronal support cells called astrocytes sharply
slows disease progression in mice.
The study, conducted in the laboratory of Don Cleveland, Ph.D., UCSD
Professor of Medicine, Neurosciences and Cellular and Molecular
Medicine and member of the Ludwig Institute for Cancer Research, is
published in Nature Neuroscience.
'Mutant genes that cause ALS are expressed widely, not just in the
motor neurones,' Cleveland explained. 'Targeting the partner cells
like astrocytes, which live in a synergistic environment with the
neurone cells, helps stop the 'cascade of damage.' Therapeutically,
this is the big news.'
ALS is a progressive disease that attacks the motor neurones, long
and complex nerve cells that reach from the brain to the spinal cord
and from the spinal cord to the muscles throughout the body, which
act to control voluntary movement. Degeneration of the motor neurones
in ALS leads to progressive loss of muscle control, paralysis and
untimely death. Estimated to affect some 30,000 Americans, most
people are diagnosed with ALS between the ages of 45 and 65.
Typically, ALS patients live only one to five years after initial
diagnosis.
In findings published in Science in June 2006, Cleveland and his
colleagues showed that in early stages of inherited ALS, small immune
cells called microglia are damaged by mutations in the SOD1 protein,
and that these immune cells then act to significantly accelerate the
degeneration of the motor neurones. The new study demonstrates that
much the same thing happens to astrocytes, support cells that are
essential to neuronal function, and whose dysfunction is implicated
in many diseases. The researchers speculate that the non-neuronal
cells play a vital role in nourishing the motor neurones and in
scavenging toxins from the cellular environment. As with microglia,
the helper role of astrocytes is altered due to mutations in the SOD1
protein.
'We tested what would happen if we removed the mutant gene from
astrocytes in mouse models,' said Cleveland. 'What happened was it
doubled the lifespan of the mouse after the onset of ALS.'
Astrocytes are key components in balancing the neurotransmitter
signals that neurones use to communicate. To examine whether mutant
SOD1 damage to the astrocytes contributes to disease progression in
ALS, researchers in the Cleveland lab used a genetic trick to excise
the mutant SOD1 gene, but only in astrocytes. Reduction of the
disease-causing mutant SOD1 in astrocytes did not slow disease onset
or early disease; however, the late stage of the disease was
extended, nearly doubling the normal life expectancy of a mouse with
ALS.
'Silencing the mutant gene in the astrocytes not only helps protect
the motor neurone, but delays activation of mutant microglia that act
to accelerate the progression of ALS,' said Cleveland.
The findings show that mutant astrocytes are likely to be viable
targets to slow the rate of disease spread and extend the life of
patients with ALS. Cleveland added that this may prove especially
important news to researchers in California and elsewhere working
with stem cells. 'This gives scientists a good idea of what cells
should be replaced using stem cell therapy. Astrocytes are very
likely much easier to replace than the slow-growing motor neurone.'
Additional contributors to the study include Koji Yamanaka, Seung Joo
Chun and Severine Boillee, Ludwig Institute for Cancer Research and
UCSD Department of Medicine and Neuroscience; Noriko Fujimore-Tonou
and Hirofumi Yamashita, Yamanaka Research Unit, RIKEN Brain Science
Institute, Saitama, Japan; David H. Gutmann, Department of Neurology,
Washington University, St. Louis; Ryosuke Takahashi, Department of
Neurology, Kyoto University, Japan; and Hidemi Misawa, Department of
Pharmacology, Kyoritsu University of Pharmacy, Tokyo.
The work was supposed by grants from the National Institutes of
Health, the Packard ALS Centre at Johns Hopkins University, the
Muscular Dystrophy Association, the Uehara Memorial Foundation, the
Nakabayashi Trust for ALS Research, and the Ministry of Education,
Culture, Sports Science and Technology of Japan.
Source: University of California, San Diego Health Sciences
http://www.sciencec
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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