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A Gene’s Many Jobs in the Brain
  
By Edward R. Winstead

Scientists have employed a new technique to test the function of a particular gene in different regions of the mouse brain.

It is now possible, they show, to see what happens to mice when the same gene is impaired but in different areas of the brain.

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“With this technique you can ask, ‘What does gene ‘X’ do in region A and region B?’” says Ralph J. DiLeone of University of Texas Southwestern Medical Center in Dallas, who led the research.

The new technique could be used to create mice that have localized damage to brain cells, as do people with Parkinson’s disease.

“Our goal is to develop a system that allows us to manipulate the brain,” says DiLeone, who hopes that this strategy will reveal insights about how the human brain works. Using mice, his laboratory investigates the brain’s response to rewarding stimuli, such as food or drugs like amphetamines.

DiLeone and his colleagues inhibited a gene involved in the production of dopamine in two groups of mice. They observed distinct changes in the animals depending on which brain region was affected.

One group of mice developed motor difficulties like those seen in mouse models of Parkinson’s disease, which is associated with a loss of dopamine. The other group had an abnormal response to amphetamines.

The researchers used a technique known as RNA interference, in which RNA is added to cells to inhibit a gene. The RNA, packaged inside viruses, was delivered to mouse brain cells surgically. The effect on the gene lasted about two months after the surgery. The results appear in Nature Medicine.

For decades researchers have tested the functions of genes by breeding mice that lack a particular gene and observing the effects on the animals. But some genes cannot be tested this way because the mice die before they are born or prematurely. RNA interference is cheaper and more efficient than breeding mutant mice.

The virus in the study was an adeno-associated virus, or AAV. This virus is able to get into neurons and has potential to be used to deliver therapeutic genes in people. For instance, in 2002 researchers used AAV to deliver genetic material to people with the blood disease hemophilia B.

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Hommel, J.D. et al. Local gene knockdown in the brain using viral-mediated RNA interference. Nat Med 9, 1539-1544 (December 2003).

 

Manno, C.S. et al. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood 101, 2963-2972 (April 15, 2003).

 

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