image: Some unusual alliances are necessary for you to wiggle your fingers, researchers report. Understanding those relationships should enable better treatment of neuromuscular diseases, such as myasthenia gravis, which prevent muscles from taking orders from your brain, said Dr. Lin Mei, director of the Institute of Molecular Medicine and Genetics at Georgia Health Sciences University. view more
Credit: Phil Jones, GHSU Photographer
Augusta, Ga. – Some unusual alliances are necessary for you to wiggle your fingers, researchers report.
Understanding those relationships should enable better treatment of neuromuscular diseases, such as myasthenia gravis, which prevent muscles from taking orders from your brain, said Dr. Lin Mei, Director of the Institute of Molecular Medicine and Genetics at Georgia Health Sciences University.
During development, neurons in the spinal cord reach out to muscle fibers to form a direct line of communication called the neuromuscular junction. Once complete, motor neurons send chemical messengers, called acetylcholine, via that junction so you can text, walk or breathe.
As a first step in laying down the junction, motor neurons release the protein agrin, which reaches out to LRP4, a protein on the muscle cell surface. This activates MuSK, an enzyme that supports the clustering of receptors on the muscle cell surface that will enable communication between the brain and muscle. The precise alignment between the neuron and muscle cell that occurs during development ensures there is no confusion about what the brain is telling the muscle to do.
A missing piece was how agrin and LRP4 get together.
A study published in the journal Genes & Development shows that in the space between the neuron and its muscle cell, agrin and LRP4 first form two diverse work teams: each team has one agrin and one LRP4. The two teams then merge to form a four-molecule complex essential to MuSK activation and to the clustering of receptors that will receive the chemical messenger acetylcholine on the muscle cell.
It was expected that the two agrins would get together first then prompt the LRP4s to merge. "This is very novel," said Mei, and an important finding in efforts to intervene in diseases that attack the neuromuscular junction.
Mei and Dr. Rongsheng Jin, neuroscientist and structural biologist in the Del E. Webb Neuroscience, Aging and Stem Cell Research Center at Sanford-Burnham Medical Research Institute in La Jolla, Calif., are co-corresponding authors of the study.
Myasthenia gravis, which paralyzes previously healthy individuals, targets these protein workers. The condition, which can run in families, likely results from a process called mimicry in which the immune system starts making antibodies to the workers, which it confuses with a previous viral or bacterial infection. The majority of patients have antibodies to acetylcholine receptors and a smaller percentage have antibodies to MuSK. Most recently, GHSU researchers also helped identify LRP4 as an antibody target.
The scientists already are looking at the impact of the antibodies on the LRP4 complex. Understanding its unique structure is essential to designing drugs that could one day block such attacks. "Prior to this we had no idea how they interacted," Mei said.
In addition to providing new information on muscle diseases, this study might also have a far-reaching ripple effect in the field of neuroscience.
"This is just the beginning," says Jin. "Now that we know more about how signals are transferred during the formation of neuromuscular junctions, we can start looking at how a similar system might work in brain synapses and how it malfunctions in neurodegenerative conditions like Alzheimer's and Parkinson's diseases. If we can figure out how to trigger the formation of new brain synapses, maintain old synapses, or simply slow their disappearance, we'd be much better equipped to prevent or treat these diseases."
To reveal the novel mechanism, researchers used a technique known as X-ray crystallography, which produces 3-D "pictures" of protein at the atomic level using powerful X-ray beams.
Jin is the recipient of the Alfred P. Sloan Research Fellowship and the Human Frontier Science Program Young Investigator research grant. Mei is a Georgia Research Alliance Eminent Scholar in Neuroscience. Collaborators include Dr. Kay Perry in the Department of Chemistry and Chemical Biology at Cornell University's and the U.S. Department of Energy's Argonne National Laboratory.
About Georgia Health Sciences University
Georgia Health Sciences University is the state's public academic health center. The enterprise includes the Medical College of Georgia and the Colleges of Allied Health Sciences, Dental Medicine, Graduate Studies and Nursing as well as Georgia Health Sciences Medical Center and Georgia Health Sciences Children's Medical Center. GHSU is a unit of the University System of Georgia and an equal opportunity institution. For more information, visit http://www.georgiahealth.edu.
About Sanford-Burnham Medical Research Institute
Sanford-Burnham Medical Research Institute is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. The Institute consistently ranks among the top five organizations worldwide for its scientific impact in the fields of biology and biochemistry (defined by citations per publication) and currently ranks third in the nation in NIH funding among all laboratory-based research institutes. Sanford-Burnham is a highly innovative organization, currently ranking second nationally among all organizations in capital efficiency of generating patents, defined by the number of patents issued per grant dollars awarded, according to government statistics.
Sanford-Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is especially known for its world-class capabilities in stem cell research and drug discovery technologies. Sanford-Burnham is a U.S.-based, non-profit public benefit corporation, with operations in San Diego (La Jolla), Santa Barbara, and Orlando (Lake Nona). For more information, please visit our website (www.sanfordburnham.org) or blog (http://beaker.sanfordburnham.org). You can also receive updates by following us on Facebook and Twitter.
Journal
Genes & Development