Oct. 14, 2008 Over the past several decades, many laboratories have studied the communication between nerve cells and muscle fibers that are crucial to form and maintain neuromuscular synapses. Now, researchers at the at the NYU Langone Medical Center have found that a protein named Lrp4 is the missing link that allows communication between two crucial molecules—one derived from the nerve and the other from muscle—that enables the formation of the synapse.
These findings (Lrp4 is a Receptor for Agrin and Forms a Complex with MuSK), which may lead to new insights into the causes of numerous neurological diseases, including myasthenia gravis and ALS (Lou Gehrig's Disease), are published in the on-line edition of the journal Cell .
Steven J. Burden Ph.D., coordinator for the molecular neurobiology program and professor of pharmacology and cell biology at the Skirball Institute for Biomolecular Medicine led the study with his colleague, Natalie Kim, and is available to discuss this discovery.
"This paper is a major advance in understanding the development of the neuromuscular junction. It solves the long-standing mystery of what Agrin binds to at the developing junction to activate the receptor tyrosine kinase MuSK," says molecular biologist Martin Raff of the MRC laboratory for Molecular Cell Biology, University College, London.
"The study unambiguously identifies the Lrp4 protein as an essential component of the Agrin receptor, along with MuSK. It is especially appropriate that the breakthrough has come from the Burden laboratory, as Burden has been studying the neuromuscular junctions for almost all of his scientific career and has been involved in the Agrin and MuSK stories from their beginnings: it seems only right that such persistence is rewarded."
"Our ability to move and breathe depends upon the special connection between nerve cells and skeletal muscle fibers - the 'neuromuscular synapse,'" explains Dr. Burden.
"Making a neuromuscular synapse requires many steps. Once motor axons find the muscle fiber, they must instruct the muscle to organize 'molecular antennae' consisting of receptors for the neurotransmitter acetylcholine, which is released from nerve cells and stimulates muscle contraction. Deficiencies in any of these steps are responsible for multiple diseases that impair movement. Work by many groups, both basic science and clinical, over several decades, has been dedicated to understanding the instructions, which pass between nerve cells and muscle fibers, that are essential to form and maintain neuromuscular synapses.
"Previous studies demonstrated that a specific molecule on the surface of the muscle fiber, called MuSK, is critical in relaying instructions from motor neurons. Likewise, previous studies showed that a molecule called Agrin is the instruction from these nerve cells. The missing link in the field has been how Agrin 'talks' to MuSK. Our paper reports that Lrp4, a member of the low density lipoprotein receptor family of molecules, is this missing link. This long awaited discovery opens many avenues and may lead to even greater insights into underlying causes of numerous neurological diseases."
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