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Genetic model for devastating form of paraplegia suggests new treatments

ey have discovered that spastin is highly enriched in nerve cells, especially in the synapses--the junctions between pairs of nerve cells and between nerve and muscle cells. Using advanced genetic engineering methods to manipulate gene dosage, their study showed that either too much or too little of the enzyme disrupts microtubule stability, degrading the nerve cells' ability to function. They also found that pharmacological treatments that counteracted these destabilizing effects restored normal nerve function.

"These findings suggest that HSP is caused primarily through impaired regulation of the nerve cell cytoskeleton," says Broadie, professor of biological sciences and pharmacology and an investigator at the Kennedy Center for Research on Human Development. "Spastin, as well as other HSP-linked genes, appears to mediate this common function. This suggests that treatment of this common defect may be effective for many, perhaps most, HSP patients."

The organism that the researchers used in the study is the fruit fly, Drosophila melanogaster, the "lab rat" of genetics research. "Drosophila is the perfect organism to study complex genetic diseases like HSP," says Vanderbilt graduate student Nick Trotta, who is the first author on the paper. "All we need to know is what gene is involved and we can change the way the gene is expressed within a few weeks. That lets us replicate the conditions associated with the disease so we can learn more about how it works."

At the molecular level, there is very little difference between a Drosophila neuron and a human neuron, Trotta says. For example, fruit flies have a protein called D-Spastin that performs the same functions as human spastin. The two enzymes are 48 percent identical and 60 percent similar at the amino acid level.

"It may seem surprising that a fly can be used to uncover the molecular basis of human disease, but it has been shown over and over again in the last several decades that insights ga
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Contact: David F. Salisbury
david.salisbury@vanderbilt.edu
615-343-6803
Vanderbilt University
15-Jul-2004


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