EDITOR'S PICK: Immune system turns on the body in narcolepsy
Individuals with the sleep disorder narcolepsy suffer with
excessive daytime sleepiness and attacks of muscle paralysis
triggered by strong emotions (a condition known as cataplexy). It
is thought that narcolepsy is an autoimmune disorder — that
is, it is caused by the individual's immune system attacking
certain cells in the body — but this has not yet been proven
definitively. However, Mehdi Tafti and colleagues, at the
University of Lausanne, Switzerland, have now identified
autoantibodies (immune molecules that target a natural protein in
the body rather than a protein from an infectious agent) that
target the natural protein Trib2 in narcolepsy patients with
cataplexy, suggesting that narcolepsy is indeed an autoimmune
disorder.
TITLE: Elevated Tribbles homolog 2–specific antibody
levels in narcolepsy patients
AUTHOR CONTACT:
Mehdi Tafti
Center for Integrative Genomics, University of Lausanne, Lausanne,
Switzerland.
Phone: 4121.692.3971; Fax: 4121.692.3965; E-mail:
mtafti@unil.ch.
View this article at:
http://www.jci.org/articles/view/41366?key=99222230093dc63d46b3
EDITOR'S PICK: New therapeutic target for most common solid
cancer in childhood?
A team of researchers, led by Patrick Mehlen, at
Université de Lyon, France, has identified the protein NT-3
and the cell-surface molecule to which it binds (TrkC) as potential
therapeutic targets for the treatment of neuroblastoma — the
most frequent solid tumor in young children— by studying
human neuroblastoma cells in vitro and after xenotransplantation
into mice and chicks.
In the study, NT-3 was found to be expressed at increased levels
in aggressive human neuroblastomas and to block the ability of TrkC
to induce tumor cell death by a process known as apoptosis. In
vitro analysis of human neuroblastoma cell lines indicated that
both decreasing NT-3 expression and culturing in the presence of an
antibody that blocked NT-3 binding to TrkC triggered the cells to
undergo apoptosis. More importantly, blocking the NT-3/TrkC
interaction inhibited tumor growth and metastasis in both a chick
and a mouse xenograft model of neuroblastoma. The authors therefore
suggest that disrupting the NT-3/TrkC interaction might provide a
new approach to treating neuroblastoma, a form of cancer for which
treatment options are currently limited.
TITLE: Neurotrophin-3 production promotes human neuroblastoma
cell survival by inhibiting TrkC-induced apoptosis
AUTHOR CONTACT:
Patrick Mehlen
CNRS UMR5238, Université de Lyon, Lyon, France.
Phone: 33.4.78.78.28.70; Fax: 33.4.78.78.28.87; E-mail:
mehlen@lyon.fnclcc.fr.
View this article at:
http://www.jci.org/articles/view/41013?key=7f26b0d679e4415a781a
DEVELOPMENT: Deciphering the role of the protein RET in
development
Several diseases and developmental defects, including
Hirschsprung disease and congenital anomalies of kidneys or urinary
tract (CAKUT) syndrome, are caused by mutations in the RET gene. It
is not clear, however, how RET gene mutations lead to such a range
of diseases, which can occur in isolation or combination. Insight
into this issue has now been provided by Sanjay Jain and
colleagues, at Washington University School of Medicine, St. Louis,
through their analysis of ten strains of RET mutant mice.
Specifically, it was determined that different RET-stimulated
signaling pathways control the development of the genitourinary
system and the enteric and autonomic nervous systems. This
conclusion suggests that an individual's disease symptoms are
determined by which signaling pathways are disrupted by the RET
gene mutation that the individual carries.
TITLE: Organotypic specificity of key RET adaptor-docking sites
in the pathogenesis of neurocristopathies and renal malformations
in mice
AUTHOR CONTACT:
Sanjay Jain
Washington University School of Medicine, St. Louis, MO, USA.
Phone: 314.454.8728; Fax: 314.454.7735; E-mail:
sjain22@wustl.edu.
View this article at:
http://www.jci.org/articles/view/41619?key=badb101cbe87ee404e42
VASCULAR BIOLOGY: Inflammation contributes to blood vessel
disease in neurofibromatosis type 1
Neurofibromatosis type 1 (NF1) is an inherited tumor disorder
caused by mutations in the NF1 gene. Individuals with NF1 have any
one of a number of clinical symptoms, including learning
difficulties, eye problems, and epilepsy. They also often develop
blood vessel disease that can result in blood vessels becoming
blocked, although how this symptom of NF1 develops has not been
determined. But now, by studying mice that model NF1 and humans
with NF1, David Ingram Jr and colleagues, at Indiana University
School of Medicine, Indianapolis, have generated genetic and
cellular evidence that chronic inflammation contributes to the
development of blood vessel disease in patients with NF1. The
authors therefore suggest that future studies should focus on
harnessing this information to develop potential new avenues for
therapeutic and diagnostic purposes.
TITLE: Genetic and cellular evidence of vascular inflammation in
neurofibromin-deficient mice and humans
AUTHOR CONTACT:
David A. Ingram Jr.
Indiana University School of Medicine, Indianapolis, IN, USA.
Phone: 317.278.8245; Fax: 317.274.8679; E-mail:
http://www.jci.org/articles/view/41443?key=26a44908c078cddbbede
NEPHROLOGY: Role for the protein Sat1 in kidney stones and liver
toxicity
A team of researchers, at the University of Queensland,
Australia, has studied the function of the protein Sat1 in mice and
determined that it is likely to have an important role in
acetaminophen-induced liver toxicity (the most common cause of
acute liver failure in the Western world) and urolithiasis (a
condition in which stones are present in the urinary system,
including the kidneys and bladder).
Kidney and urinary stones and liver toxicity are linked to
alterations in oxalate and sulfate homeostasis, respectively. The
team, led by Daniel Markovich, generated mice lacking Sat1, a
mediator of oxalate and sulfate transport that is localized to the
kidney, liver, and intestine. Sat1-deficient mice excreted excess
amounts of oxalate in their urine (a common symptom in individuals
with calcium oxalate kidney stones) and had calcium oxalate stones
in their kidney tubules and bladder. These mice also excreted
excess amounts of sulfate in their urine and exhibited enhanced
acetaminophen-induced liver toxicity. The authors therefore
conclude that Sat1 maintains appropriate levels of oxalate and
sulfate and may be critical to the development of calcium oxalate
kidney and urinary stones and acetaminophen-induced liver
toxicity.
TITLE: Urolithiasis and hepatotoxicity are linked to the anion
transporter Sat1 in mice
AUTHOR CONTACT:
Daniel Markovich
University of Queensland, St. Lucia, Queensland, Australia.
Phone: 61.7.3365.1400; Fax: 61.7.3365.1766; E-mail:
d.markovich@uq.edu.au.
View this article at:
http://www.jci.org/articles/view/31474?key=35d3e1718eeb05731035
METABOLIC DISEASE: How the protein WFS1 stops pancreatic beta
cells stressing out
Individuals with the inherited disorder Wolfram syndrome develop
a form of diabetes known as insulin-dependent diabetes mellitus,
which is caused by loss of cells in the pancreas that produce the
hormone insulin (beta cells), and suffer from neurological
dysfunctions. One form of Wolfram syndrome is caused by mutations
in the WFS1 gene, which produces the protein WFS1. Previous studies
have shown that the normal function of WFS1 is to protect against a
cellular process known as ER stress, but exactly how it does this
was not known. However, a team of researchers, led by Fumihiko
Urano, at the University of Massachusetts Medical School,
Worcester, has now identified the signaling pathway by which WFS1
negatively regulates ER stress. Importantly, this signaling pathway
was dysregulated in pancreatic beta cells from mice lacking WFS1
and immune cells from patients with Wolfram syndrome, leading the
authors to conclude that unresolved ER stress in the pancreatic
beta cells of individuals with Wolfram syndrome leads to their loss
and the development of insulin-dependent diabetes mellitus.
TITLE: Wolfram syndrome 1 gene negatively regulates ER stress
signaling in rodent and human cells
AUTHOR CONTACT:
Fumihiko Urano
University of Massachusetts Medical School, Worcester, MA,
USA.
Phone: 508.856.6012; Fax: 508.856.4650; E-mail:
http://www.jci.org/articles/view/39678?key=83b34b29fda6ae4ec6bd
METABOLIC DISEASE: Two proteins with opposing roles in
regulating energy balance
A team of researchers, led by Kendra Bence, at the University of
Pennsylvania, Philadelphia, has identified two proteins with
opposing roles in the regulation of energy balance by nerve cells
in the brain and spinal cord of mice known as POMC neurons.
In the study, mice lacking the protein PTP1B only in POMC
neurons (POMC-Ptp1b–/– mice) had decreased fat content
and expended more energy than normal mice. By contrast, mice
lacking the protein SHP2 only in POMC neurons
(POMC-Shp2–/– mice) had increased fat content and
expended less energy than normal mice. Underlying these data was
the fact that POMC-Ptp1b–/– mice were able to control
glucose levels in their blood easily, whereas
POMC-Shp2–/– mice were not. These data indicate that
PTP1B and SHP2 have reciprocal roles in POMC-neuron regulation of
energy balance, at least in mice.
TITLE: PTP1B and SHP2 in POMC neurons reciprocally regulate
energy balance in mice
AUTHOR CONTACT:
Kendra K. Bence
University of Pennsylvania, Philadelphia, PA, USA.
Phone: 215.746.2998; Fax: 215.573.5186; E-mail:
kbence@vet.upenn.edu.
View this article at:
http://www.jci.org/articles/view/39620?key=165b87c2feba4a3c8de1
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