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UCSF study points to link to neurodegenerative disease target

September 02, 2005

A UCSF study has found that a specific signaling link between neurons and muscles in the fruit fly is essential for keeping the insect's nervous system stable.

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

"If we want to make new drugs to treat neurodegenerative disease, then we have to identify new drug targets, and our study findings present that potential," he says. "This study is a significant step forward because we have shown that a signaling system composed of several genes is 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 for the entire life of the organism, and understanding how the myriad patterns and pathways of these connections are maintained for long periods of time presents an ongoing challenge to scientists, says Davis.

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

In the absence of BMP signaling, their research showed, the synapse between the nerve and muscle disassembles and degenerates. This observation enabled the team to look for new genes involved in the BMP signaling system, which led to the identification of specific stabilizing factors in the nervous system.

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

By examining genetic mutations that delete individual genes, the scientists were able to demonstrate that BMP signaling is required for the stability of synaptic connections. Further genetic tests demonstrated that a cytoplasmic enzyme called LIM Kinase1 is an essential link that enables BMP signaling molecules to stabilize the synapse.

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

"The signaling molecules that are present in fruit flies are basically the same as in humans," explains Davis. "In a matter of a few years we hope to test the function of every gene in the genome and identify a whole array of genes that are necessary to keep the neuromuscular synapse stable."

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

"With ALS and other neuromuscular degenerative diseases, only a handful of genes have been identified that either cause the diseases or contribute to their progression."

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

University of California-San Francisco