JCI table of contents: Nov. 1, 2006

EDITOR'S PICK: Lack of GBA2: a contraceptive for male mice

Although it had previously been thought that a protein known as GBA2 was important for bile acid metabolism, a new study appearing in the November issue of the Journal of Clinical Investigation shows that in mice GBA2 is in fact required for male fertility. This study might explain the contraceptive effect in mice of a treatment for humans lacking the related protein GBA1 and could lead to the development of a new male contraceptive.

To gain insight into the function of GBA2, David Russell and colleagues generated mice lacking GBA2. Surprisingly, given that it had been proposed that GBA2 had a role in regulating a key step in the metabolism of bile acid, bile acid metabolism in these mice occurred normally. Instead, male mice lacking GBA2 showed decreased fertility. This was because the sperm from these mice had abnormally large, round heads, and were fewer in number and moved more slowly than sperm from normal mice.

Individuals lacking the GBA2 related protein GBA1 suffer from Gaucher's disease (a disease that causes various symptoms, including enlarged internal organs and neurologic defects) and one treatment for this disease has been shown to decrease fertility in mice. This study, identifying a crucial role in male fertility for GBA2, might help explain the effect on fertility of this treatment for Gaucher's disease and, as Martin Matzuk and colleagues explain in an accompanying commentary, might help further the development of a nonhormonal male contraceptive pill.

TITLE: Mutation of beta-glucosidase 2 causes glycolipid storage disorder disease and impaired male fertility


David W. Russell
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 648-2007; Fax (214) 648-6899; E-mail: david.russell@utsouthwestern.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29224


TITLE: Shaping the sperm head: an ER enzyme leaves its mark


Martin M. Matzuk
Baylor College of Medicine, Houston, Texas, USA.
Phone: (713) 798-6451; Fax: (713) 798-5833; E-mail: mmatzuk@bcm.tmc.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30221

EDITOR'S PICK: Decreased TGF-beta signaling might make you demented

The physical changes that occur in the brain of patients with Alzheimer's disease (AD), the most common cause of dementia in the elderly, have been well characterized, but the cause(s) of this disease and the development of therapies has remained elusive. Now, in a study appearing in the November issue of the Journal of Clinical Investigation, researchers from Stanford University have shown that decreased signaling through a receptor known as T-beta-RII -- expression of which is decreased in the neurons of patients with AD -- increases neurodegeneration in mice.

Tony Wyss-Coray and colleagues found that neuron expression of T-beta-RII is decreased at an early stage of disease in the brains of individuals with AD. So they generated mice in which signaling by the molecule that triggers T-beta-RII, TGF-beta, is decreased. Analysis of these mice showed age-dependent neurodegeneration and beta-amyloid peptide accumulation in the brain, as is seen in the brain of patients with AD. The authors therefore suggest that increasing TGF-beta signaling in the brain might reduce neurodegeneration and be of benefit to individuals with AD.

In an accompanying commentary, Pritam Das and Todd Golde from the Mayo Clinic in Jacksonville outline how a decrease in TGF-beta signaling in the brain might promote neurodegeneration and beta-amyloid peptide accumulation, but warn that further studies to determine what causes the decreased expression of T-beta-RII are required.

TITLE: Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer's pathology


Tony Wyss-Coray
Stanford University, Stanford, California, USA.
Phone: (650) 852-3220; Fax: (650) 849-0434; E-mail: twc@stanford.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=27341


TITLE: Dysfunction of TGF-beta in Alzheimer's disease


Todd Golde
Mayo Clinic Jacksonville, Jacksonville, Florida, USA.
Phone: (904) 953-2538; Fax: (904) 953-7370; E-mail: tgolde@mayo.edu.

Pritam Das
Mayo Clinic Jacksonville, Jacksonville, Florida, USA.
Phone: (904) 953-1086; Fax: (904) 953-7117; E-mail: das.pritam@mayo.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30284

EDITOR'S PICK: Gene therapy a possibility for metachromatic leukodystrophy?

Metachromatic leukodystrophy (MLD) is an inherited disease that causes progressively more severe neurological defects that result in death early in life. Individuals with MLD have a genetic defect that means they lack a protein known as ARSA. There are currently no therapies for MLD, largely because the barrier between the blood supply and brain -- which tightly regulates the substances that can enter the brain -- provides an obstacle that has yet to be overcome. In a study appearing in the November issue of the Journal of Clinical Investigation, Alessandra Biffi and colleagues from the San Raffaele Scientific Institute in Italy, now show that the neurological defects in mice lacking ARSA can be corrected by treatment with hematopoietic stem progenitor cells (HSPCs) genetically modified to express high levels of ARSA. Importantly, ASRA was detected in the neurons of the treated mice and was derived from microglial cells, which differentiate from HSPCs. The successful correction of the protein defect in neurons and of the neurological defects led the authors to suggest that HSPC gene therapy might be efficacious for the treatment of individuals with MLD.

In an accompanying commentary, Harald Neumann, from the University of Bonn in Germany, suggests that studies to determine whether microglial cells could be used as vehicles for gene therapy for other genetic defects affecting the brain should be undertaken.

TITLE: Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice


Alessandra Biffi
San Raffaele Scientific Institute, Milan, Italy.
Phone: +39-02-2643-4681; Fax: +39-02-2643-4668; E-mail: biffi.alessandra@hsr.it.

Luigi Naldini
San Raffaele Scientific Institute, Milan, Italy.
Phone: +39-02-2643-4681; Fax: +39-02-2643-4668; E-mail: luigi.naldini@hsr.it.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28873


TITLE: Microglia: a cellular vehicle for CNS gene therapy


Harald Neumann
University of Bonn, Bonn, Germany.
Phone: +49-228-6885-541; Fax: +49-228-6885-501; E-mail: hneuman1@uni-bonn.de.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30230

PULMONARY: Lung DCs legitimate targets for treating asthma

Allergic asthma is caused by an unwanted immune response known as a Th2 cell response. Most treatments for asthma currently target this Th2 cell response and its downstream effects. However, immune cells known as dendritic cells (DCs) are crucial activators of all T cell responses, including the Th2 cell response in asthma, so therapies that target DC function in the airways might represent a new way to treat individuals with allergic asthma.

Now, in a study appearing in the November issue of the Journal of Clinical Investigation, Bart Lambrecht and colleagues from Erasmus University, The Netherlands, have shown that inhalation of the immunosuppressive drug FTY720 suppresses the symptoms of allergic asthma in a mouse model of the disease. Inhalation of FTY720 suppressed the allergic Th2 cell response in the lungs by preventing lung DCs from leaving the lungs and going to the site at which they activate the allergic Th2 cell response. This demonstration that targeting lung DCs can suppress allergic asthma in mice might open new avenues of research for the development of drugs that target DC function to treat individuals with allergic asthma.

TITLE: Local application of FTY720 to the lung abrogates experimental asthma by altering dendritic cell function.


Bart N. Lambrecht
Erasmus University Medical Center, Rotterdam, The Netherlands.
Phone: +31-10-408-7703; Fax: +31-10-408-9453; E-mail: b.lambrecht@erasmusmc.nl.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28295

PHYSIOLOGY: Prostaglandin E helps plug a hole after birth

In the fetus, a blood vessel known as the ductus arteriosus (DA) is essential for fetal life. However, this blood vessel is detrimental for life outside the womb and it normally closes after birth. Failure of the DA to close after birth results in a congenital heart condition known as patent DA (PDA), a condition that is a major problem for premature babies. Although the soluble factor prostaglandin E (PGE) is required to keep the DA open during fetal life, mice lacking the PGE receptor EP4 develop fatal PDA. A study appearing in the November issue of the Journal of Clinical Investigation now sheds light on this paradox by showing that EP4 is required for one of the processes that must occur for the DA to close.

Susumu Minamisawa and colleagues from Yokohama University, Japan, used several different approaches to show that in mice, EP4 signals are required for the in utero formation of a plug (known as the intimal cushion) that begins the process of closing the DA. Current treatment for PDA, the administration of drugs that inhibit the production of PGE (COX inhibitors), are less effective at inducing closure of the DA in severely premature babies than in near-term babies. This study, suggests that this decrease in effectiveness is likely to be due to the lack of formation of the intimal cushion and provides a rationale for developing strategies to stimulate intimal cushion formation to treat babies with PDA.

In an accompanying commentary, Kathryn Ivey and Deepak Srivastava from the University of California San Francisco discuss the clinical implications of this study and describe how it might help explain why the use of COX inhibitors by women who are pregnant increases the risk of PDA.

TITLE: Chronic activation of the prostaglandin receptor EP4 promotes hyaluronan-mediated neointimal formation in the ductus arteriosus


Susumu Minamisawa
Yokohama City University, Yokohama, Japan.
Phone: +81-45-787-2575; Fax: +81-45-788-1470; E-mail: sminamis@med.yokohama-cu.ac.jp.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28639


TITLE: The paradoxical patent ductus arteriosus


Deepak Srivastava
University of California San Francisco, San Francisco, California, USA.
Phone: (415) 734-2716; Fax: (415) 355-0141; E-mail: dsrivastava@gladstone.ucsf.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30349

PHYSIOLOGY: NF-kappa-B contributes to muscle wasting

Muscle wasting is a widespread problem for individuals of all ages. It can be caused by genetic defects, such as the genetic defect that causes Duchenne muscular dystrophy, as well as be a secondary consequence of other diseases, such as cancer and diseases of the immune system. However, the molecular events that lead to muscle wasting are not well defined, meaning that treatments for this disease have not been developed.

Now, in a study appearing in the November issue of the Journal of Clinical Investigation, Foteini Mourkioti and colleagues at the European Molecular Biology Laboratory (EMBL) Mouse Biology Unit in Monterotondo-Scalo, Italy, have shown that the muscles of mice lacking the protein IKK2 (which is required for activation of a regulator of gene expression NF-kappa-B) in muscle cells were stronger than the muscles of normal mice. Furthermore, mice lacking IKK2 in muscle cells were protected against muscle wasting caused by either denervation or exposure to a toxin. These data indicate that IKK2 activation of NF-kappa-B is one molecular pathway that leads to muscle wasting and cause the authors to suggest that agents targeting this pathway might have potential as therapeutics for the treatment of muscle wasting

In an accompanying commentary, Michael Karin -- from the University of California San Diego -- suggests that because NF-kappa-B is a key regulator of gene expression during inflammation, inflammation might have a pathogenic role in muscle degenerative disease and that anti-inflammatory therapies might prove beneficial to individuals with such diseases.

TITLE: Targeted ablation of IKK2 improves skeletal muscle strength, maintains mass, and promotes regeneration


Foteini Mourkioti
European Molecular Biology Laboratory (EMBL) Mouse Biology Unit, Monterotondo-Scalo, Italy.
Phone: +39-06-90091-214; Fax: +39-06-90091-272; E-mail: fmourkioti@embl-monterotondo.it.

Anna-Lynn Wegener

Press Officer
EMBL, Heidelberg, Germany
Phone : +49-6221-3878452 ; Fax +49-6221-387525 ; E-mail: wegener@embl.de.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28721


TITLE: Role for IKK2 in muscle: waste not, want not


Michael Karin

University of California San Diego, La Jolla, California, USA.
Phone: (858) 534-1361; Fax: (858) 534-8158; E-mail: karinoffice@ucsd.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30268

METABOLIC DISEASE: Why PCSK9 raises cholesterol levels

Some individuals have increased activity of a protein known as PCSK9 because they have a mutation in one of their genes encoding this protein. This genetic defect causes individuals to have high levels of cholesterol in their blood. Although it is known that this is because PCSK9 decreases the number of receptors that remove cholesterol from the blood (LDLRs) expressed by cells in the liver, the mechanisms by which this occurs have not been previously determined. Now, in a study appearing in the November issue of the Journal of Clinical Investigation, researchers at the University of Texas Southwestern have shown that PCSK9 functions to decrease LDLR levels from outside the cell.

Jay Horton and colleagues found that PCSK9 bound to LDRLs on the surface of liver cells and caused the LDLRs to be internalized. Importantly, PCSK9 in the blood system of one mouse was able to decrease the levels of LDLR found at the surface of liver cells of another mouse, causing cholesterol levels to rise. Because this study shows that PCSK9 in the blood regulates the level of LDLR expressed by liver cells, the authors suggest that blocking PCSK9 function in the blood might provide a new approach for developing drugs to treat individuals with high levels of cholesterol.

TITLE: Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice


Jay D. Horton
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 648-9677; Fax: (214) 648-8804; E-mail: jay.horton@utsouthwestern.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29383


Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
    Published on PsychCentral.com. All rights reserved.



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