Koji Yamanaka & Don W.
Cleveland talk with ScienceWatch.com and answer a
few questions about this month's Fast Breaking Paper in the
field of Neuroscience & Behavior. The authors have also
sent along images of their work.
Article Title: Astrocytes as determinants of
disease progression in inherited amyotrophic lateral
sclerosis
Authors: Yamanaka,
K;Chun, SJ;Boillee, S;Fujimori-Tonou, N;Yamashita,
H;Gutmann, DH;Takahashi, R;Misawa,
H;Cleveland,
DW
Journal: NAT NEUROSCI, Volume: 11, Issue: 3, Page: 251-253,
Year: MAR 2008
* Univ Calif San Diego, Ludwig Inst Canc Res, 9500 Gilman
Dr, La Jolla, CA 92093 USA.
* Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA
92093 USA.
* Univ Calif San Diego, Dept Med & Neurosci, La Jolla,
CA 92093 USA.
(addresses have been truncated)
Why do you think your paper is highly
cited?
Glial cells have long been regarded as a supporting player of
neurodegenerative diseases, which are characterized by a progressive,
selective death of a certain group of neurons. However, our research
identified a specific glial cell type, the astrocyte, as a therapeutic
target for amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's
disease), a neurodegenerative disease affecting adult motor neurons. This
finding has a broad impact on other neurodegenerative disease research such
as that regarding Alzheimer's , Parkinson's and Huntington's disease in
which causative gene products are expressed ubiquitously (that is, in both
neurons and their neighboring glial cells).
Coauthor:
Don W. Cleveland
Furthermore, recent advances in stem cell research will make it feasible to
treat neurodegenerative diseases using renewable cells, including
astrocytes. Our research provides a proof-of-principle for the
transplantation of healthy astrocytes (or astrocyte precursors) to slow
disease progression in ALS.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
Familial forms of ALS are associated with dominant mutations in the gene
for Cu/Zn superoxide dismutase (SOD1). Human ALS disease is well
recapitulated in the mouse expressing an ALS-linked mutant SOD1 gene. While
the mutant SOD1 gene is expressed in all cells, mutant SOD1 mice develop
selective motor neuron death.
To identify the cell types which are crucial for neurodegeneration, we
developed a new ALS mouse model carrying a mutant SOD1 transgene that can
be removed by the action of Cre recombinase. We initially published this
mouse in 2006 (Boillée S, Yamanaka K, et al. "Onset and
progression in inherited ALS determined by motor neurons and microglia,"
Science 312[5778]: 1389-92, 2006) and used selective gene
inactivation in motor neurons and microglia to identify mutant damage
within them as key determinants of disease onset and progression,
respectively. In our current paper, we identified astrocytes as a key
determinant of disease progression.
Would you summarize the significance of your paper in
layman's terms?
ALS-linked SOD1 mutations provoke toxicity to motor neurons through an
unknown mechanism. Although expression of mutant SOD1 in all cell types
causes selective motor neuron death, the key damage from the mutant protein
had been widely predicted to arise within the motor neurons.
What we have shown is that two types of glia cells, astrocytes, a
supporting cell type that plays a principal role in brain repair and
maintenance, and microglia, the resident immune cells within the nervous
system, develop the damage responsible for accelerating disease
progression.
This inflammatory process was further exacerbated in the environment where
more mutant astrocytes were populated, leading to accelerated disease
progression. Our results document that an appropriate therapy targeting
either astrocytes or microglia would slow disease progression.
Where do you see your research leading in the
future?
In the short term, we will try to uncover exactly how the mutant SOD1
damages astrocytes and microglia so as to drive rapid disease progression.
This is a crucial goal for devising therapies to ameliorate the underlying
damage.
Do you foresee any social or political implications for
your research?
ALS is one of the most intractable diseases and no viable therapy is
currently available. There is increasing demand to find a cure for ALS, not
only from the patients' point of view but also from society and politics,
since a significant amount of cost and personnel resources are required for
ALS patient care. Our research provided an important key step to find a
cure for ALS: identifying glial cells as attractive targets for a treatment
that can slow disease progression.
Koji Yamanaka, MD, Ph.D.
Unit Leader
Yamanaka Research Unit
RIKEN Brain Science Institute
Wako, Saitama, Japan Web
Don W. Cleveland, Ph.D.
Head, Laboratory for Cell Biology
Ludwig Institute for Cancer Research
Professor and Chair, Department of Cellular and Molecular Medicine
University of California, San Diego
La Jolla, CA, USA Web
KEYWORDS: MOTOR-NEURONS; EXTEND SURVIVAL; RAT MODEL; ALS; MICE;
MICROGLIA.