Genetic model for devastating form of paraplegia suggests new ...( ined from Drosophila studies provide im...)

ined from Drosophila studies provide immediate insight into the human condition. There is a long history of Drosophila research pioneering major breakthroughs in our understanding of fundamental biological problems," says Broadie. To study how spastin functions in living neurons, the researchers designed transgenic flies with altered amounts of D-Spastin protein in their neurons and analyzed the effects.

Animals with lower levels of D-Spastin were weak, exhibited coordination defects and died prematurely. At the cellular level, the researchers found that the reduction of D-Spastin caused synapses to fill with ultra-stable microtubules. As a consequence, synapses were structurally reduced in size and showed profoundly altered communication properties.

Flies with heightened levels of D-Spastin were also sick. High levels of over-expression caused embryonic death. Lower levels caused nerve cell death (neurodegeneration.) Even very low levels of over-expression caused adults to be slow and weak. Within the nerve cells, the researchers found that too much D-Spastin caused stable microtubules to disappear altogether. At the synapse, elevated levels of spastin also caused a large drop in synaptic signal strength, impairing nerve communication.

These studies showed that spastin concentrates in synapses, where it acts locally to destabilize microtubules. Moreover, the researchers found that specific drugs that alter microtubule stability remedy the defects that occur in synaptic function as a result of changes in spastin levels. In both loss and over-expression cases, the researchers found that treatment with drugs that correct microtubule stability defects caused the synaptic signal strength to rebound to normal levels. This result suggests that drugs that stabilize microtubule activity might provide a new approach for treating HSP.

The Vanderbilt researchers were funded by the National Institutes of Health and the Italian researchers by the Telethon F
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Contact: David F. Salisbury
david.salisbury@vanderbilt.edu
615-343-6803
Vanderbilt University
15-Jul-2004

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