UCSF Study Finds Signaling Link In Fruit Fly Nervous System May Point To Target For Treating Neurodegenerative Disease

The findings are relevant for ongoing research in identifying causesand developing treatments for neuromuscular neurodegenerative diseasesin humans, such as amyotrophic lateral sclerosis (ALS), also known asLou Gehrig's disease, says study co-author Graeme Davis, PhD, associateprofessor and vice chair of the Department of Biochemistry andBiophysics at the University of California, San Francisco.

"If we want to make new drugs to treat neurodegenerative disease, thenwe have to identify new drug targets, and our study findings presentthat potential," he says. "This study is a significant step forwardbecause we have shown that a signaling system composed of several genesis important for keeping the nervous system stable."

The findings are reported in the September issue of the journal Neuron.

The nervous system is a complex pattern of connections that exists forthe entire life of the organism, and understanding how the myriadpatterns and pathways of these connections are maintained for longperiods of time presents an ongoing challenge to scientists, saysDavis.

Davis and co-author Benjamin Eaton, PhD, a post-doctoral fellowin Davis' lab, were led to the new discovery through ongoingexperiments with a signaling system in fruit flies that is tied to aprotein called bone morphogenetic protein, or BMP. They found that theBMP signaling system is required for the long-term stability of theneuromuscular synapse, the point where a nervous impulse passes from aneuron to a muscle to cause muscle movement.

In the absence of BMP signaling, their research showed, the synapsebetween the nerve and muscle disassembles and degenerates. Thisobservation enabled the team to look for new genes involved in the BMPsignaling system, which led to the identification of specificstabilizing factors in the nervous system.

"It is a very complicated task to keep the nervous system stable. Weare using a model organism, the fruit fly, to help us rapidly identifythe genetic basis for the long-term stability," Davis says. "What wehave been able to do with this study is to hone in on several genesthat are essential for this stability."

By examining genetic mutations that delete individual genes, thescientists were able to demonstrate that BMP signaling is required forthe stability of synaptic connections. Further genetic testsdemonstrated that a cytoplasmic enzyme called LIM Kinase1 is anessential link that enables BMP signaling molecules to stabilize thesynapse.

Davis notes that working with fruit flies allows scientists to identifythe function of new genes very rapidly. "We can easily observe theconnections between the nerve and muscle, and see if the nerve isdegenerating. Each week we can test hundreds of genes and determine ifthey are important for stabilizing the synapse between the nerve andmuscle."

"The signaling molecules that are present in fruit flies are basicallythe same as in humans," explains Davis. "In a matter of a few years wehope to test the function of every gene in the genome and identify awhole array of genes that are necessary to keep the neuromuscularsynapse stable."

ALS, for example, is a degenerative neuromuscular disease. "If we canfind a way to keep the neuromuscular synapse stable, then we might beable to slow down the rate of degeneration," he adds.

"With ALS and other neuromuscular degenerative diseases, only a handfulof genes have been identified that either cause the diseases orcontribute to their progression."

"The exciting thing about this study," says Davis, "is that it startsto tell us how we can keep a synapse stable. And that can lead us tounderstanding why synapses degenerate at the muscle cells of peoplewith ALS. If we can identify more genes that are important for synapsestability, then there will be more targets for the development of newdrugs to treat these diseases. Currently, the number of potentialtargets for new drug development is quite limiting and we hope to helpchange that. This is an exciting time with the potential for realprogress in terms of understanding the biology of these diseases."