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News From The Journal Of Clinical Investigation
Main Category: Biology / Biochemistry
Also Included In: Neurology / Neuroscience; Eye Health / Blindness; Ear, Nose and Throat
Article Date: 25 Jan 2008 - 5:00 PST

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Understanding a cause of Lou Gehrig's disease

Amyotrophic lateral sclerosis (ALS), often known as Lou Gehrig's disease, is the most common adult-onset motor neuron disease. Although most cases of ALS arise randomly, a sizeable proportion of individuals inherit the disease. Among these inherited cases, mutations in the SOD1 gene are the most frequently identified cause. A new study in mice, by John Engelhardt and colleagues at Iowa University, Iowa City, has identified a new mechanism by which SOD1 mutations associated with ALS can alter normal cellular function and trigger cell damage. As there is no known cure for ALS, the authors hope that these data might provide potential targets for the development of drugs to treat individuals with ALS caused by mutations in the SOD1 gene.

In the study, SOD1 was shown to regulate the production of the potentially dangerous oxygen radical superoxide by a protein known as Nox. In normal cells, SOD1 was found to bind and stabilize an activator of Nox known as Rac1, as concentrations of superoxide and the product to which it is converted, hydrogen peroxide, increased SOD1 dissociated from Rac1 and Nox stopped making superoxide. However, mutant forms of SOD1 found in individuals with ALS never dissociated from Rac1 and so Nox never stopped making superoxide. Treating mice that develop an ALS-like disease because they have been engineered to express an ALS-associated mutant form of SOD1 with the inhibitor of Nox apocynin decreased disease and increased their lifespan. However, as discussed in an accompanying commentary by Séverine Boillée and Don Cleveland from the University of California at San Diego, there are several questions that need to be addressed before the potential of apocynin as a human therapeutic can be determined.

TITLE: SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model

AUTHOR CONTACT:
John F. Engelhardt
Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.

ACCOMPANYING COMMENTARY TITLE: Revisiting oxidative damage in ALS: microglia, Nox, and mutant SOD1

AUTHOR CONTACT:
Don W. Cleveland
University of California at San Diego, La Jolla, California, USA.

Genetic link to one form of a very common pediatric illness - inflammation of the middle ear

Inflammation of the middle ear (otitis media) is one of the most common pediatric ailments. Young children are particularly prone to otitis media as their Eustachian tubes, which regulate the pressure in the middle ear, have not yet fully developed. In many instances it is accompanied by an acute ear infection and can be resolved by a course of antibiotics. However, other forms of the disease, e.g, otitis media with effusion, which occurs when fluid accumulates in the middle-ear cavity in the absence of an acute ear infection, are linked to auditory or eustachian tube dysfunction. This, in turn, is influenced by poorly understood factors, including genetics.

In a new study, J. G. Seidman and colleagues at Harvard Medical School in Boston, found that removing the Eya4 gene in mice caused malformation of the Eustachian tube as well as otitis media with effusion. The authors therefore suggested that EYA4 mutations might predispose individuals to otitis media with effusion. As discussed in an accompanying commentary by Evelyn Lazaridis and James Saunders at the University of Pennsylvania, Philadelphia, this description of a genetic model of otitis media with effusion should aid in the development of therapeutics for this condition, frequent recurrence of which is accompanied by an increased risk for sustained conductive hearing loss, with the potential for speech, language, and learning problems.

TITLE: Eya4-deficient mice are a model for heritable otitis media

AUTHOR CONTACT:
J. G. Seidman
Harvard Medical School, Boston, Massachusetts, USA.

ACCOMPANYING COMMENTARY TITLE: Can you hear me now? A genetic model of otitis media with effusion

AUTHOR CONTACT:
Evelyn Lazaridis
University of Pennsylvania, Philadelphia, Pennsylvania, USA.

I can see clearly now Epo has come and gone

Erythropoietin (Epo) is a hormone that stimulates red blood cell production and that is used to treat individuals who are anemic, including individuals who are anemic and have diseases of the eye caused by pathologic new blood vessel growth in the retina, such as diabetic retinopathy (DR) and retinopathy of prematurity. However, high levels of Epo have been found in the eye of individuals who are not anemic but who have DR, meaning that the relationship between Epo and retinopathies is not well defined. A new study by Lois Smith and her colleagues at Children's Hospital, Boston, has now revealed a highly timing-dependent role for Epo in this disease process in mice.

Retinopathy occurs in two phases that are characterized by blood vessel loss and growth, respectively. In this study, Epo deficiency during early retinopathy was shown to contribute to retinal blood vessel loss in mice, and Epo treatment reduced this loss. In contrast, late Epo treatment exacerbated retinal disease by enhancing blood vessel growth. The authors have therefore recommended careful monitoring of Epo therapy in patients at risk for retinopathy, particularly diabetics. As early treatment with Epo also protected mice from retinal nerve cell death, Maria Grant and colleagues suggested in an accompanying commentary that Epo might prove a novel treatment for neurovascular damage, but they caution that its timing must be carefully regulated to prevent adverse effects.

TITLE: Erythropoietin deficiency decreases vascular stability in mice

AUTHOR CONTACT:
Lois E. H. Smith
Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.

ACCOMPANYING COMMENTARY TITLE: Erythropoietin: when liability becomes asset in neurovascular repair

AUTHOR CONTACT:
Maria B. Grant
University of Florida, Gainesville, Florida, USA.

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Article adapted by Medical News Today from original press release.
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Source: Karen Honey
Journal of Clinical Investigation

http://www.medicalnewstoday.com/articles/95169.php