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Vol. LX, No. 22
October 31, 2008
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Reverse Animal Model
NICHD Scientists Discover Mouse Disorder, Search for Human Analog

On the front page...

Traditionally, researchers have developed animal models in hopes of gaining insight into human disorders. Dr. Tracey Rouault has reversed this approach. She has developed a strain of mice with a fatal disorder of iron metabolism. She is now searching for people with the human version of the mouse disorder.

“We know which gene is affected,” Rouault said. “We have a treatment that would likely be beneficial. Now we need to find out if anyone has it.”

Continued...


  Dr. Tracey Rouault  
  Dr. Tracey Rouault  

Animal models—long a research mainstay—are lab animals that have been altered in some way to develop a condition resembling a human illness. But because the human disorders are sometimes not well understood, the animal models often only approximate the human disorders. For example, mice designed to mimic amyotrophic lateral sclerosis may correspond to only a minority of cases. Similarly, a mouse model for Alzheimer’s disease develops some of the brain changes seen in the disorder, but doesn’t develop the memory loss and dementia characteristic of that condition.

NICHD researcher Rouault disabled a mouse gene for iron metabolism. She and her colleagues in the section on human iron metabolism have found that mice lacking the gene develop a progressive, and ultimately fatal, neurological condition. Moreover, her team has even discovered how to treat the condition.

The mouse disorder affects the nervous system, causing tremors, weakness in the limbs and a form of anemia that cannot be treated. The disorder results from disabling the gene for iron regulatory protein 2 (IRP2), which regulates how much iron is in a cell. Human beings with a mutation in this gene might have been incorrectly diagnosed as having Parkinson’s disease or some other neurological disorder that causes tremors and impairs movement.

Mice lacking the gene for iron regulatory protein 2 develop tremors, weakness in the limbs and a form of anemia that cannot be treated. People with a mutation in this gene may have been misdiagnosed as having Parkinson’s disease or some other neurological disorder.
Mice lacking the gene for iron regulatory protein 2 develop tremors, weakness in the limbs and a form of anemia that cannot be treated. People with a mutation in this gene may have been misdiagnosed as having Parkinson’s disease or some other neurological disorder.

In 2001, Rouault and her colleagues discovered that mice lacking the gene for IRP2 developed iron deposits in the brain, tremors and weakness in the limbs. In 2005, the researchers discovered that the mice had anemia and other blood abnormalities.

In a study published online recently in the Proceedings of the National Academy of Sciences, Rouault and her coworkers reported that the antioxidant compound Tempol can restore normal iron metabolism to the animals. If given early enough, Tempol can arrest the nervous system deterioration and prevent symptoms from getting worse.

The researchers are also studying whether treatment with Tempol can reverse nervous system damage that has already occurred.

Tempol works by activating iron regulatory protein 1 (IRP1). Rouault said that IRP1 and IRP2 have the same function—both proteins regulate how much iron is in a cell. Although iron is a nutrient, too much can be toxic. For this reason, cells have intricate biochemical machinery to prevent iron from building up to lethal levels. IRP1 and IRP2 govern the actions of various other proteins involved in iron metabolism.

Normally, IRP2 fulfills this regulatory function unassisted and the gene for IRP1 remains dormant. Tempol, however, activates IRP1 so that it too can regulate iron in the cell.

When IRP2 is disabled, all of the iron is taken up by a cellular protein known as ferritin. Normally, ferritin stores iron temporarily, releasing it when it is needed. But mice lacking IRP2 manufacture too much ferritin. Consequently, the cell is deprived of the iron it needs to carry out biological function.

IRP1 is bound to a chemical compound—known as an iron sulfur cluster—that keeps the gene inactive. Tempol chemically removes the iron sulfur cluster and allows IRP1 to regulate iron metabolism. When given to mice that can’t produce IRP2, Tempol stimulates the activity of IRP1. The activated IRP1 reduces ferritin production to normal levels and prevents the nervous system damage that results from reduced levels of iron.

In their article, Rouault and her coworkers noted the location of the corresponding human gene for IRP2 in a particular area of chromosome 15 (15q25). She said the location may assist researchers studying neurological disorders. It’s possible that some research teams have collected samples of genetic material from families with neurological conditions. An analysis of these samples may lead to the identification of people with mutations in IRP2.

Patients with generalized neurological impairment and anemia that doesn’t respond to treatment may have their physicians contact Rouault at Rouault@mail.nih.gov or write her at the Molecular Medicine Program, NICHD, Bldg. 18T, Rm. 101, Bethesda, MD 20892. NIHRecord Icon

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