Download Neurodegenerative disease: neurons don`t take all of the blame for

RESEARCH HIGHLIGHTS
Disease Models & Mechanisms
Disease Models & Mechanisms DMM
Neurodegenerative
disease: neurons don’t take
all of the blame for ALS
Amyotrophic lateral sclerosis (ALS) is a
progressive, neurodegenerative disease resulting in paralysis and usually death within
less than 5 years of onset. Inherited forms
of ALS are most often associated with expression of a dominant mutated form of superoxide dismutase (SOD1) which is toxic
to motor neurons, causing them to die prematurely.
To determine the role of mutated SOD1
in the progression of ALS, Yamanaka et al.
engineered a chimeric mouse model in
which the expression of mutant SOD1 was
isolated to motor neurons and oligodendrocytes. They report that the presence of
the surrounding ‘normal’ cells, not expressing mutated SOD1, inhibits the progression of neurodegeneration and increases disease-free life span when
compared with mice that ubiquitously
express mutant SOD1.
This indicates that many different cell
types, in addition to motor neurons and
oligodendrocytes, contribute to the onset
and progression of ALS and the interaction of cell types should be considered
when determining the potential of future
therapeutics.
A C-type lectin domain family 5
(CLEC5A) on the surface of macrophages
has now been identified that interacts with
an envelope protein on the dengue virus
to specifically induce the production
of proinflammatory cytokines by
macrophages during infection. A collaboration of researchers in Taiwan used a
monoclonal antibody to block CLEC5A,
and demonstrate that inhibiting this
macrophage-virus interaction prevents
plasma leakage and hemorrhage in a
mouse model. The antibody had an overall
pro-survival effect suggesting that this
strategy may prove effective for inhibiting
severe inflammation and shock associated
with certain viral infections.
TORC, which stimulates CREB activation
in the brain during starvation. Their recent
report illustrates that TORC mutant flies
are more sensitive to oxidative stress and
starvation and exhibited reduced stores of
carbohydrates and fat. Thus, TORC is necessary to maintain normal energy balance
in flies.
TORC genes (target of rapamycin
(TOR) complexes) are highly conserved
and orthologs exist in organisms ranging
from algae to humans and recent studies
show an important role for TOR kinases in
metabolism and aging in yeast. Thus,
related kinases may prove important in
human glucose metabolism and oxidative
stress response.
Chen, S. T., Lin, Y. L., Huang, M. T., Wu, M. F., Cheng,
S. C., Lei, H. Y., Lee, C. K., Chiou, T. W., Wong, C. H.
and Hsieh, S. L. (2008). CLEC5A is critical for denguevirus-induced lethal disease. Nature 453, 672-676.
Wang, B., Goode, J., Best, J., Meltzer, J., Schilman, P.
E., Chen, J., Garza, D., Thomas, J. B. and Montminy,
M. (2008). The insulin-regulated CREB coactivator TORC
promotes stress resistance in Drosophila. Cell Metab. 7,
434-444.
Metabolism: TORCing
neurons to maintain blood
glucose
Yamanaka, K., Boillee, S., Roberts, E. A., Garcia, M. L.,
McAlonis-Downes, M., Mikse, O. R., Cleveland, D. W.
and Goldstein, L. S. (2008). Mutant SOD1 in cell types
other than motor neurons and oligodendrocytes
accelerates onset of disease in ALS mice. Proc. Natl.
Acad. Sci. USA 105, 7594-7599.
Image courtesy of Matthew Freeman.
Infectious disease: taking
the shock out of
hemorrhagic fever
Some of the most deleterious effects associated with dengue-virus infection
result from induction of proinflammatory
cytokines and overstimulation of the
immune system. Cytokines make blood
vessels leaky and promote inflammation
of tissues, which can lead to internal hemorrhaging and loss of blood fluid from
the vasculature, which can result in
shock. Macrophages are a major producer of proinflammatory cytokines and
a primary target of dengue virus
infection.
Disease Models & Mechanisms
Insulin serves as a master switch to finely
regulate circulating glucose levels despite
regular intervals of fasting and eating, by
manipulating signaling pathways. Glucose
homeostasis requires the generation and
maintenance of glycogen and lipid stores
that are utilized in times of fasting or starvation.
Low levels of circulating glucose in
Drosophila and mammals causes the evolutionarily conserved signaling protein,
cAMP response element-binding protein
(CREB), to stimulate the production of
glucose from noncarbohydrate sources,
such as fat or amino acids. Collaborative
work between researchers at UCSD,
Novartis and the Salk Institute have identified a CREB coactivator in Drosophila,
Heart disease and stem
cells: new sources of hope
for troubled hearts
Two distinct populations of cells have
previously been identified as cardiac
progenitors, giving rise to different areas
of the developing heart. Scientists in the
USA and the UK have now come together
to add a third myocardial lineage to the
list.
A recent report from Cai et al. has identified pluripotent cardiac cells in mice that
develop into myocytes in the heart wall in
addition to cardiac fibroblasts and coronary smooth muscle cells. These stem
cells originate in the proepicardium and
express the T-box transcription factor
Tbx18, which is also found at sites of heart
regeneration in zebrafish.
The identification of new cardiac stem
cell populations should lead to better understanding the mechanisms underlying
heart development and congenital defects.
As we accumulate information on how
these cells maintain pluripotency and differentiate, they may play an important role
in regenerative medicine for congenital
defects or acquired heart disease.
Cai, C. L., Martin, J. C., Sun, Y., Cui, L., Wang, L.,
Ouyang, K., Yang, L., Bu, L., Liang, X., Zhang, X.,
Stallcup, W. B., Denton, C. P., McCulloch, A., Chen, J.
and Evans, S. M. (2008). A myocardial lineage derives
from Tbx18 epicardial cells. Nature May 14 [Epub ahead
of print] [doi 10.1038].
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RESEARCH HIGHLIGHTS
Cancer: cilia, cysts and
renal cell carcinoma
Disease Models & Mechanisms
tion. Although the mechanisms by which
these pathways are activated in VHL patients are incompletely understood, this
opens the possibility that inhibition of PI3K
or ERK signaling pathways may prove effective therapeutic strategies to prevent the
loss of primary cilia and inhibit cyst formation and ccRCC formation in VHL patients.
Frew, I. J., Thoma, C. R., Georgiev, S., Minola, A.,
Hitz, M., Montani, M., Moch, H. and Krek, W. (2008).
pVHL and PTEN tumour suppressor proteins
cooperatively suppress kidney cyst formation. EMBO J.
May 22 [Epub ahead of print] [doi:
10.1038/emboj.2008.96].
Disease Models & Mechanisms DMM
Image reproduced from Development (2005) 132,
(12).
Mutations in the von Hippel-Lindau tumor
suppressor gene (VHL) predispose patients
to develop both renal cysts and clear cell
renal cell carcinoma, albeit with relatively
low frequency, a finding that has been recapitulated in mice mutant for the Vhlh
gene. This has led to the view that additional mutations are required to cause progression to cysts or carcinoma in VHL
disease. Work in the lab of Wilhelm Krek
and colleagues at ETH Zurich shows that
cysts from patients with VHL disease
exhibit increased activation of phosphoinositide 3-kinase (PI3K). Because the Pten
tumor suppressor normally antagonizes
PI3K signaling, they combined conditional
inactivation of both the Vhlh and Pten
tumor suppressor gene in the mouse
kidney, and found this caused cyst formation after short latency. Interestingly, the
cells lining these cysts frequently lacked a
primary cilium, a structure thought to be
involved in suppressing cellular prolifera-
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Neurodegenerative
disease: cleaning out
Alzheimer’s by autophagy
Autophagy (literally, self-eating) is a major
cellular pathway by which long-lived cellular proteins, protein aggregates, and organelles are degraded. Proteins targeted for
destruction by this pathway are first recruited into double-membrane vesicles
called autophagosomes, and are delivered
from there to lysosomes. Beclin 1 is critical
for autophagosome formation, and mutant
mice heterozygous for a deletion of beclin 1
show reduced autophagosome production.
Alzheimer’s disease, like other neurodegenerative diseases, is characterized by the
presence of protein aggregates and the presence of autophagosomes in dystrophic neurites; however, whether autophagy is protective or detrimental is unclear. In an
international collaboration including researchers from Stanford University,
Image reproduced from J. Cell Sci. (2007) 120, (23).
University of California, San Diego, Freie
Universitaet Berlin, Columbia University,
University of Texas Southwestern Medical
Center, and the VA Palo Alto Heath Care
System, Pickford et al. present a series of experiments suggesting that reduced beclin 1
decreases neuronal autophagy and exacerbates the Alzheimer’s-like phenotypes of
APP transgenic mice. Thus, autophagy may
be protective and increasing beclin-1 levels
may provide therapeutic benefit in
Alzheimer’s disease.
Pickford, F., Masliah, E., Britschgi, M., Lucin, K.,
Narasimhan, R., Jaeger, P. A., Small, S., Spencer, B.,
Rockenstein, E., Levine, B. and Wyss-Coray, T. (2008).
The autophagy-related protein beclin 1 shows reduced
expression in early Alzheimer disease and regulates
amyloid beta accumulation in mice. J. Clin. Invest. 118,
2190-2199.
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