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Journal of Clinical Investigation

JCI online early table of contents: March 1, 2010

EDITOR'S PICK: Staying alive: insufficient vitamin C causes perinatal lethality in mice

Vitamin C is indispensible for life: without it, an individual develops the fatal disease scurvy. We obtain all our vitamin C from out diet and several tightly regulated processes control the level of vitamin C in our bodies. One protein known to be involved in controlling vitamin C levels is Slc23a1, but the in vivo importance of this has not been determined. However, Mark Levine and colleagues, at the NIH, Bethesda, have now identified several crucial functions for Slc23a1 in mice. For example, Slc23a1 had a key role in absorption of vitamin C by the kidney and in perinatal survival. Although the data on perinatal survival are provocative, the authors warn that appropriate clinical data need to be collected before it can be determined whether low levels of vitamin C in women who are pregnant contribute to either perinatal morbidity or mortality.

TITLE: Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice

AUTHOR CONTACT:
Mark Levine
National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
Phone: 301.402.5588; Fax: 301.402.6436; E-mail: markL@mail.nih.gov.

View this article at: http://www.jci.org/articles/view/39191?key=e001e4095d59a712cded


EDITOR'S PICK: Overcoming multidrug resistance in acute lymphoblastic leukemia cells

Acute lymphoblastic leukemia (ALL) most commonly affects children, in whom there is an overall cure rate of 85%. A strong predictor of poor outcome is resistance to chemotherapy with glucocorticoids. Such resistance is caused, at least in part, by an inability of the leukemic cells to die by a process known as mitochondrial apoptosis. Many researchers are therefore trying to find ways to overcome the block in mitochondrial apoptosis in glucocorticoid-resistant leukemic cells. Jean-Pierre Bourquin and colleagues, at the University of Zurich, Switzerland, have now identified a way to do just that, showing that this approach resensitizes multidrug-resistant childhood ALL cells to glucocorticoids and other cytotoxic agents.

The authors found that treating multidrug-resistant childhood ALL cells with the drug obatoclax, which is under development for the treatment of both cancer and leukemia, resensitized them to glucocorticoids and other cytotoxic agents. Further analysis indicated that this reversal of glucocorticoid resistance occurred through rapid activation of a process known as autophagy-dependent necroptosis, bypassing the block in mitochondrial apoptosis. As the levels of obatoclax required to achieve these effects were not themselves toxic to the cells, the authors suggest that their data provide the rationale for treating individuals with multidrug-resistant ALL in a similar way.

TITLE: Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance

AUTHOR CONTACT:
Jean-Pierre Bourquin
University Children's Hospital Zurich, University of Zurich, Switzerland.
Phone: 41.44.266.7304; Fax: 41.44.266.7171; E-mail: jean-pierre.bourquin@kispi.uzh.ch.

View this article at: http://www.jci.org/articles/view/39987?key=4e895dead848910ba5a2


NEUROBIOLOGY: Common mechanism for more than 50% of cases of hereditary spastic paraplegia

Hereditary spastic paraplegia (HSP) is the name given to a group of inherited neurological disorders characterized by progressive stiffness or tightness of the muscles (spasticity) in the lower limbs. Although mutations at over 40 genetic sites have been shown to cause HSP, more than 50% of HSP cases are caused by mutations in one of just three genes: SPG3A, which makes the protein atlastin-1; SPG31, which makes the protein REEP1; and SPG4, which makes the protein spastin. New research, performed by Craig Blackstone and colleagues, at the NIH, Bethesda, has now determined that a single mechanism is likely to underlie HSP caused by mutations in any of these three genes. Specifically, the in vitro data generated by Blackstone and colleagues indicate that atlastin-1, spastin, and REEP1 interact within a cellular compartment known as the tubular ER membrane in nerve cells that connect the cerebral cortex of the brain and the spinal cord to coordinate ER shaping and ER interactions with a cellular structure known as the microtubule cytoskeleton and that defects in these processes underlie the more than 50% of HSP cases caused by mutations in SPG3A, SPG31, and SPG4.

TITLE: Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network

AUTHOR CONTACT:
Craig Blackstone
National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA.
Phone: 301.451.9680; Fax: 301.480.4888; E-mail: blackstc@ninds.nih.gov.

View this article at: http://www.jci.org/articles/view/40979?key=417dc2992f2e4ce34ecb


NEPHROLOGY: Kidney diseases linked to the cellular process autophagy

A leading contributor to the development of both diseases that affect a structure in the kidney known as the glomerulus (glomerular diseases) and kidney failure is injury and loss of kidney cells known as podocytes. New research, performed by Tobias Huber and colleagues, at University Hospital Freiburg, Germany, has now determined that podocyte integrity in mice is maintained by the cellular process autophagy.

In the study, mouse podocytes were found to naturally undergo high levels of autophagy. Furthermore, deletion of the gene autophagy-related 5 in podocytes led to podocyte loss and glomerular disease in aging mice and to increased susceptibility to models of glomerular disease in young mice. The authors therefore suggest that autophagy helps protect against podocyte aging and glomerular injury and that it could be targeted to reduce human glomerular disease and aging-related loss of kidney function.

TITLE: Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice

AUTHOR CONTACT:
Tobias B. Huber
University Hospital Freiburg, Freiburg, Germany.
Phone: 49.761.270.3559; Fax: 49.761.270.3270; E-mail: tobias.huber@uniklinik-freiburg.de.

View this article at: http://www.jci.org/articles/view/39492?key=2dbcb05f33dffe58467c


IMMUNOLOGY: Uncovering the in vivo role of the protein DO

Using a mouse model of type 1 diabetes, Lisa Denzin and colleagues, at Sloan-Kettering Institute, New York, have clearly defined the in vivo biological role of the immune system protein DO, something that had not been well characterized before.

Immune cells known as CD4+ T cells are triggered to mount a response when they recognize a peptide in association with a protein complex known as MHCII. The peptide repertoire associated with MHCII therefore has a key role in determining what CD4+ T cells are triggered. If a CD4+ T cell recognizes an MHCII complex associated with peptides derived from proteins in the body then the CD4+ T cell is triggered to attack the body, leading to autoimmune diseases such as type 1 diabetes. In their study, Denzin and colleagues provide clear evidence to support the hypothesis that the protein DO modulates the repertoire of peptides associated with MHCII such that fewer of the peptides are derived from proteins in the body and thus the development of autoimmunity is suppressed. They therefore suggest that modulating the MHCII-associated peptide repertoire might provide a way to treat and/or prevent autoimmune disease.

TITLE: Targeted regulation of self-peptide presentation prevents type I diabetes in mice without disrupting general immunocompetence

AUTHOR CONTACT:
Lisa K. Denzin
Sloan-Kettering Institute, New York, New York, USA.
Phone: 646.888.2333; Fax: 646.422.0470; E-mail: denzinl@mskcc.org.

View this article at: http://www.jci.org/articles/view/40220?key=218410309e61f1d7ff29

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