News Release

JCI table of contents: February 15, 2006

Peer-Reviewed Publication

JCI Journals

EDITOR'S PICK: Protein inhibitor tangles with Alzheimer's disease

Mayo Clinic researchers have now shown that a drug that inhibits the function of the protein Hsp90 reduces brain levels in mice of the protein tau, the abnormal accumulation of which has been implicated in the pathogenesis of Alzheimer's disease (AD). The study appears online on February 15 in advance of publication in the March print issue of the Journal of Clinical Investigation.

A hallmark of AD is the abnormal accumulation of phosphorylated tau (p-tau) proteins resulting in the formation of neurofibrillary tangles, which impair the function of brain axons. Enhancing the removal of these p-tau proteins may therefore be a relevant therapeutic strategy. In the current study, Leonard Petrucelli and colleagues from the Mayo Clinic showed that a complex of two proteins, CHIP and Hsp90 (which are involved in protein refolding and degradation), plays a role in alleviating p-tau accumulation in mice and cultured human cells. They went on to show that administration of an Hsp90 inhibitor, EC102, to mice overexpressing human tau caused a significant reduction in p-tau levels.

The findings point to a pivotal role for Hsp90 in aberrant tau degradation and potentially in tau refolding. Unlike many drugs, EC102 is able to cross the blood-brain barrier, making it a highly promising therapeutic candidate for AD and other conditions in which tau accumulates in abnormally high levels in the brain.

TITLE: The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins

AUTHOR CONTACT:
Leonard Petrucelli
Mayo Clinic College of Medicine, Jacksonville, Florida, USA.
Phone : (904) 953-2855; Fax: (904) 953-7370; E-mail: petrucelli.leonard@mayo.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=29715


EDITOR'S PICK: Proteases cause pain in irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder in the developed world. It is characterized by altered bowel function, abdominal discomfort, and pain. However, there are few effective treatments for IBS, in part because the molecular mechanisms underlying the disease symptoms have not been well defined. But now, researchers from the University of Calgary have provided evidence that serine proteases and PAR2 might provide new therapeutic targets for the treatment of IBS.

In the study, which appears online on February 15 in advance of publication in the March print issue of the Journal of Clinical Investigation, Nathalie Vergnolle and colleagues show that colonic biopsies from individuals with IBS release increased amounts of serine proteases when cultured in vitro, compared with colonic biopsies from healthy individuals. Likewise, colonic washes from individuals with IBS contained higher levels of serine proteases than did colonic washes from healthy individuals. The supernatant from cultured colonic biopsies from individuals with IBS activated mouse sensory neurons in vitro and caused mice to exhibit increased responsiveness to pain when it was administered into the colon. Both these effects were dependent on serine proteases in the supernatant and were mediated by activation of a protein known as PAR2, leading the authors to suggest that targeting serine proteases and/or PAR2 might provide sufferers of IBS with relief from their intense abdominal pain.

TITLE: Role for protease activity in visceral pain in irritable bowel syndrome

AUTHOR CONTACT:
Nathalie Vergnolle
University of Calgary, Calgary, Alberta, Canada.
Phone: (403) 220-4588; Fax: (403) 210-8195; E-mail: nvergnol@ucalgary.ca.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29255


CARDIOVASCULAR BIOLOGY: The "shear stress" of it impacts heart disease

Many different forms of heart disease can be caused by atherosclerosis (hardening or furring of the arteries). Atherosclerosis is caused by the formation of plaques that bulge into the artery, narrowing the blood vessel. One factor that determines how easily an atherosclerotic plaque forms is the shear stress that the blood flow puts on the walls of the blood vessels, with low shear stress (LSS) and oscillatory shear stress (OSS) being pro-atherogenic. But exactly how LSS and OSS mediate this pro-atherogenic effect has not be completely defined.

In a study appearing online on February 15 in advance of publication in the March print issue of the Journal of Clinical Investigation, Rob Krams and colleagues from the Erasmus Medical Center, The Netherlands, show that in mice, different types of shear stress induce the production of different soluble factors known as chemokines, and that the chemokine expression pattern influences the development of the atherosclerotic plaque. LSS was shown to induce the production of more IP-10, GRO-alpha, and fractalkine than OSS, which in fact induced no fractalkine. This correlated with differences in the composition of the atherosclerotic plaques: LSS induced plaques with thinner fibrous caps and larger necrotic cores than OSS (characteristics associated with plaque rupture, which can cause heart attacks). As blocking fractalkine function inhibited LSS-induced plaque growth and decreased plaque characteristics associated with plaque rupture, the authors suggest that targeting fractalkine might provide an effective therapy to prevent atherosclerotic plaque rupture and heart attacks.

TITLE: Shear stress–induced changes in atherosclerotic plaque composition are modulated by chemokines

AUTHOR CONTACT:
Rob Krams
Erasmus Medical Center, Rotterdam, The Netherlands.
Phone: +31-10-4087308; Fax: +31-10-4089494; E-mail: r.krams@erasmusmc.nl

View the PDF of this article at: https://www.the-jci.org/article.php?id=28180


METABOLIC DISEASE: Blood pressure heads down in the absence of PPAR-gamma

One of the most serious health conditions in the developed world is the metabolic syndrome (MetS), a collection of disorders (such as obesity and insulin resistance) that lead to increased risk of developing type 2 diabetes and heart disease. A protein known as PPAR-gamma has been shown to be affect most aspects of MetS. However, these studies have had to focus on the affects of PPAR-gamma on one aspect of MetS at a time because mice lacking PPAR-gamma in all cells die before birth. But now, Richard Morentsen, David Milstone, and colleagues have generated viable mice with a global PPAR-gamma defect and determined how the individual affects of PPAR-gamma manifest in the whole mouse.

In the study, which appears online on February 15 in advance of publication in the March print issue of the Journal of Clinical Investigation, the authors show that mice with a global PPAR-gamma defect are severely insulin resistant and have less fat than normal mice, although the latter is offset by an increase in the size of all the internal organs. These changes were associated with a decrease in blood pressure (hypotension), which is surprising given that PPAR-gamma–stimulating drugs (known as thiazolidinediones) used to treat type 2 diabetes also decrease blood pressure. These mice will therefore be useful for further investigating whether PPAR-gamma mediates the effects of thiazolidinediones in individuals with type 2 diabetes and/or MetS.

TITLE: Hypotension, lipodystrophy, and insulin resistance in generalized PPAR-gamma–deficient mice rescued from embryonic lethality

AUTHOR CONTACT:
Richard M. Mortensen
University of Michigan Medical School, Ann Arbor, Michigan, USA.
Phone: (734) 763-2021; Fax: (734) 936-8813; E-mail: rmort@umich.edu.

David S. Milstone
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 525-4308; Fax: (617) 525-4331; E-mail: milstone@rascal.med.harvard.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28859


ONCOLOGY: Profiling peripheral T cell lymphoma for clues to its pathogenesis

Peripheral T cell lymphoma, unspecified (PCTL/U) is the most common and aggressive non-Hodgkin's lymphoma that derives from neoplastic T cells. PCTL/U patients do not respond well to currently used chemotherapy. In a study appearing online on February 15 in advance of publication in the March print issue of the Journal of Clinical Investigation, Stefano Pileri and colleagues from the University of Bolgona compared the gene expression profile of PTCL/Us obtained from patient tissue with that of normal T cells and report that PCTL/Us are most closely related to either CD4+ or CD8+ activated peripheral T lymphocytes. The authors found that, compared to normal T cells, PCTL/Us display deregulation of a number of cell programs involved in tumorigenesis, including apoptosis and cell proliferation.

The authors also found that PCTL/Us aberrantly express the tyrosine kinase receptor PDGFRalpha and this receptor may therefore play a role in PCTL/U pathogenesis. They went on to show that PDGFRalpha phosphorylation was sensitive to the drug imatinib (Gleevec). PDGFRalpha inhibition should thus be examined in future clinical studies.

TITLE: Gene expression analysis of peripheral T cell lymphoma, unspecified, reveals distinct profiles and new potential therapeutic targets

AUTHOR CONTACT:
Stefano A. Pileri
University of Bologna, Bologna, Italy.
Phone : 39-051-6363044 ; Fax: 39-051-6363606; E-mail: pileri@med.unibo.it

View the PDF of this article at: https://www.the-jci.org/article.php?id=26833

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