CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development
Protein that enables our brains and muscles to talk
These findings provide insight into diseases such as muscular dystrophy, where a disconnect between brain and muscles occurs. They also point to new treatment targets according to neuroscientist Dr. Lin Mei. Mei is chairman of the Department of Neuroscience and Regenerative Medicine at the Medical College of Georgia (MCG) at Augusta University, Georgia Research Alliance Eminent Scholar in Neuroscience and corresponding author of the study appearing in the journal Neuron.
During development, neurons in the spinal cord reach out to muscle cells to form a direct line of communication. To make that connection, neurons release the protein agrin, which then connects to LRP4, a protein on the muscle cell surface. This, in turn, activates MuSK, an enzyme supporting clustering of receptors on the muscle cell surface to enable communication.
This newly discovered neddylation step occurs in one of three previously unknown parts of rapsyn function called a RING. Rapsyn's classic scaffolding function is second. A third function state is still being identified.
The RING finding is a bit of a surprise as, in biology, anchor proteins like rapsyn typically don't act this way. "This anchor is active," Mei stresses. In fact, rapsyn is the only synapse brain protein found — so far — that appears to have two essential interactions with receptors. It is known that a lot of rapsyn is found near acetylcholine receptors at neuromuscular junctures. This new finding indicates rapsyn helps ensure plenty of receptors are always present at this dynamic juncture.
Lin Mei: "Fundamentally, it provides a novel mechanism for synapse formation. Translationally, by identifying this novel enzymatic activity, presumably, one could develop a therapeutic way to make it more active."
There are still questions to be answered. Does rapsyn also change the function of receptors, as Mei suspects. Do mutations in other parts of rapsyn impact the enzymatic role of the RING domain, as there is evidence that mutations in other portions of the cycle can also lead to deadly breathing problems. Scientists are actively pursuing the function of the third rapsyn portion.
Mei is continuing to look at anchor proteins throughout the body, including in the brain. He is already examining classic anchoring proteins, such as PSD-95, in neuron-to-neuron connections, for any evidence of enzymatic activity — and potential new therapeutic targets.
Collaborators include Dr. Huabo Su, a neddylation expert in the MCG Vascular Biology Center, and Dr. Wen-Cheng Xiong, developmental neurobiologist and Weiss Research Professor in the MCG Department of Neurology.
The research was funded by the National Institutes of Health, the Department of Veterans Affairs and the National Natural Science Foundation of China.
During development, neurons in the spinal cord reach out to muscle cells to begin communication.
New research indicates the protein rapsyn ensures receptors are always making muscle to brain connections. However, defects or deletions in rapsyn can cause human fetuses to be stillborn,
likely as a result of an inability to breathe due to a failed rapsyn connection.
Image Credit: Wikipedia