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JCI online early table of contents: July 1, 2008

EDITOR'S PICK: Calpain inhibitors never forget: improving memory in Alzheimer disease mice

Overactivation of proteins known as calpains, which are involved in memory formation, has been linked to Alzheimer disease. Ottavio Arancio and colleagues, at Columbia University, New York, have now shown that two different drugs that inhibit calpains can improve memory in a mouse model of Alzheimer disease (APP/PS1 mice), leading them to suggest drugs that target calpains might stop or slow down the memory loss that occurs as Alzheimer disease progresses.

It is thought that dysfunctional signaling between nerve cells contributes to the impaired cognition experienced by individuals with Alzheimer disease. In the study, analysis of cells and tissue slices from APP/PS1 mice, specifically cells from the part of the brain known as the hippocampus and hippocampal slices, indicated that exposure to calpain inhibitors restored signaling between nerve cells to normal. The authors therefore suggest that calpain inhibitors improve memory in APP/PS1 mice because they reestablish normal signaling between nerve cells.

TITLE: Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease

Ottavio Arancio
Columbia University, New York, New York, USA.
Phone: (212) 851-4617; Fax: (212) 851-4602; E-mail:

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EDITOR'S PICK: Bringing stability to the protein defective in phenylketonuria

Phenylketonuria (PKU) is an inherited disease characterized by progressive mental retardation and seizures because the individual is deficient in the protein PAH. Most of the genetic mutations that cause PKU do so because the PAH protein that is generated by the mutated gene is not stable enough to function. New data, generated by Aurora Martinez and colleagues, at the University of Bergen, Norway, suggest that it might be possible to stabilize the mutated PAH protein in individuals with PKU such that it can function normally.

In the study, a high-throughput screen for small molecules that stabilized mutated forms of the PAH protein found in individuals with PKU identified four potential candidates. Two of these molecules were analyzed in more detail and shown to stabilize both normal and mutated PAH in their functional conformation. In addition, these molecules increased the activity and amount of normal PAH and mutated PAH expressed in human cells in vitro and increased PAH activity in the liver of mice. The authors therefore suggest that molecules that stabilize PAH (which are known as chaperones) might provide a new approach to the treatment of individuals with PKU.

TITLE: Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria

Aurora Martinez
University of Bergen, Bergen, Norway.
Phone: 47-55-58-64-27; Fax: 47-55-58-63-60; E-mail:

Javier Sancho
Universidad de Zaragoza, Zaragoza, Spain.
Phone: 00-34-976-76-1286; Fax: 00-34-976-76-2123; E-mail:

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REPRODUCTIVE BIOLOGY: FGF8 mutations linked to diseases caused by deficiency of a hormone needed for reproduction

New data, generated by Nelly Pitteloud and colleagues, at Massachusetts General Hospital, Boston, has identified mutations in the FGF8 gene in individuals with idiopathic hypogonadotropic hypogonadism (IHH), a disease characterized by failed sexual maturation and infertility due to a deficiency in the small protein gonadotropin-releasing hormone (GnRH).

Six different mutations in FGF8 were identified in individuals with IHH and were associated with slightly different symptoms and varying degrees of GnRH deficiency. When mice expressing markedly reduced levels of FGF8 (approximately 55% less than normal) were analyzed they were found to lack nerve cells producing GnRH in a region of the brain known as the hypothalamus. By contrast, mice expressing slightly more FGF8 did have nerve cells producing GnRH in the hypothalamus, although fewer than normal mice. These data led the authors to conclude that FGF8 is important for the development of nerve cells producing GnRH in both mice and humans and that mutations in FGF8 can lead to GnRH deficiency and disease in humans.

TITLE: Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice

Nelly Pitteloud
Massachusetts General Hospital, Boston, Massachusetts, USA.
Phone: (617) 724-1830; Fax: (617) 726-3537; E-mail:

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ONCOLOGY: New way to predict prostate cancer spreading

For men, one of the leading causes of death from cancer is prostate cancer that has spread to a second site (something known as metastatic prostate cancer). Defining the molecular mechanisms by which the initial tumor becomes able to spread to a new site (a process known as metastasis) is likely to help clinicians predict an individual's chance of survival and help researchers develop new therapies. New data, generated by John Martignetti and colleagues, at Mount Sinai School of Medicine, New York, has identified a specific form of the protein KLF6 (KLF6-SV1) as indicative of poor survival in men with prostate cancer.

The information in genes is converted into a protein via an intermediate known as mRNA. In the study, analysis of tumors from men with localized prostate cancer who had undergone a prostatectomy revealed that increased levels of an mRNA intermediate involved in the generation of KLF6-SV1 correlated with more rapid disease recurrence and decreased survival. Consistent with this having an important role in metastasis, prostate cancer cells expressing increased levels of KLF6-SV1 metastasized more rapidly and more often than normal prostate cancer cells in two mouse models of metastatic prostate cancer. Conversely, decreasing KLF6-SV1 expression in prostate cancer cells decreased tumor growth in mice. The authors therefore suggest that measuring KLF6-SV1 expression levels in prostate cancer tumors at the time of diagnosis might help clinicians predict whether or not the tumor will metastasize and that targeting KLF-SV1 might provide a new avenue for the development of therapeutics to treat individuals with prostate cancer.

TITLE: KLF6-SV1 overexpression accelerates human and mouse prostate cancer progression and metastasis

John A. Martignetti
Mount Sinai School of Medicine, New York, New York, USA.
Phone: (212) 659-6744; Fax: (212) 849-2638; E-mail:

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ENDOCRINOLOGY: Understanding the genetics of congenital hyperinsulinism

A number of congenital disorders characterized by low blood sugar levels (hypoglycemia) as a result of excessive secretion of the hormone insulin are collectively known as congenital hyperinsulinism. These disorders are caused by genetic mutations that result in mutant KATP channel proteins in the insulin-secreting cells of the pancreas. To develop the most common and most severe form of congenital hyperinsulinism a baby must inherit a mutated gene from each of its parents (these mutations are said to be recessive as if only one mutated gene is inherited the baby does not suffer from the disease). Recent reports have suggested that less severe forms of the disease can arise in children through the inheritance of a mutated gene from only one parent (these mutations are said to be dominant as the mutated gene causes disease despite the presence of a normal version of the gene). To better understand the differences between the recessive and dominant mutations that cause congenital hyperinsulinism, Charles Stanley and colleagues, at the Children's Hospital of Philadelphia, characterized 33 patients with dominantly inherited KATP mutations.

Consistent with the recent reports on a small number of children, the authors found that patients with disease caused by dominant mutations exhibited a milder hypoglycemia than is normal for individuals with congenital hyperinsulinism caused by recessive mutations. Indeed, there were a large number of asymptomatic individuals and disease in most symptomatic individuals was well controlled with medication. Mechanistic insight into the difference in the severity of disease caused by dominant and recessive mutations was provided by the observation that dominant mutations generated a form of KATP that can reach the cell surface but has impaired activity, whereas recessive mutations are known to generate a form of KATP that cannot reach the cell surface. The authors stress that because children with dominant KATP mutations are likely to exhibit less severe symptoms, the disease may be missed and doctors should carefully evaluate children with family histories of the disease.

TITLE: Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations

Charles A. Stanley
The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Phone: (215) 590-3420; Fax: (215) 590-1605; E-mail:

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ENDOCRINOLOGY: New insight into the mechanisms underlying congential hypothyroidism

The generation of thyroid hormones, which are essential for normal development, is dependent on the proper secretion of the protein thyroglobulin. Thyroglobuin is a large protein with several distinct regions, including one known as region I-II-III and one known as the ChEL domain. Mutations in the ChEL domain have been linked to congenital hypothyroidism. However, the exact mechanisms by which these mutations alter thyroglobulin secretion are unknown. A new study by Peter Arvan and colleagues, at the University of Michigan, Ann Arbor, has revealed that ChEL seems to have two functions that enable thryroglobulin secretion it ensures region I-II-III is folded correctly and it escorts the correctly folded protein out of the cell. The authors hope that these insights into the functions of the ChEL domain of thyroglobulin might help uncover new potential therapeutic targets for the treatment of congenital hypothyroidism.

TITLE: The cholinesterase-like domain of thyroglobulin functions as an intramolecular chaperone

Peter Arvan
University of Michigan, Ann Arbor, Michigan, USA.
Phone: (734) 936-5006; Fax: (734) 936-6684; Email:

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Contact: Karen Honey
Journal of Clinical Investigation

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