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Protein that enables our brains and muscles to talk

A huge colony of receptors must be correctly positioned and functioning on muscle cells in order to receive signals from our brains. Now a protein has been identified that helps anchor those receptors, ensuring receptor formation and function.

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.

The protein is rapsyn, and anchored receptors are for acetylcholine, a neurotransmitter that motor neurons release to activate muscle cells.

Regulation of protein ubiquitylation

University of Leicester, United Kingdom

Rapsyn is made by muscle cells as a biological anchor to attach acetylcholine receptors and ensure an ideal positioning for receipt of brain signals.

Lin Mei PhD: "For precise, efficient synapse function, receptors have to be extremely highly concentrated in exactly the right location."

The connection synapse these cells form is called a neuromuscular juncture.

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.

Mei and his collaborators have now shown that rapsyn does not just help hold receptors in place on the muscle cell, but acts as an enzyme to drive the neuromuscular juncture through a process called neddylation. Agrin and MuSK also aid neddylation.

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.

Rapsyn mutations that result in receptors not clustering, likely contribute to a wide range of muscle weakness such as seen in muscular dystrophy. Congenital myasthenic syndrome, often affects facial muscles and may first appear as drooping eyelids.

Even before identifying the function of the RING, defects or deletions specifically in rapsyn cause human fetuses to be stillborn, likely as a result of an inability to breathe. A tragic indicator of the role in development of the nerve-muscle connection.

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.

Abstract Highlights
•RING domain of rapsyn contains E3 ligase activity
•Rapsyn E3 ligase activity catalyzes neddylation as well as ubiquitination
•Agrin promotes AChR neddylation for cluster formation
•Rapsyn E3 ligase activity is required for AChR clustering and NMJ assembly

Neurotransmission is ensured by a high concentration of neurotransmitter receptors at the postsynaptic membrane. This is mediated by scaffold proteins that bridge the receptors with cytoskeleton. One such protein is rapsyn (receptor-associated protein at synapse), which is essential for acetylcholine receptor (AChR) clustering and NMJ (neuromuscular junction) formation. We show that the RING domain of rapsyn contains E3 ligase activity. Mutation of the RING domain that abolishes the enzyme activity inhibits rapsyn- as well as agrin-induced AChR clustering in heterologous and muscle cells. Further biological and genetic studies support a working model where rapsyn, a classic scaffold protein, serves as an E3 ligase to induce AChR clustering and NMJ formation, possibly by regulation of AChR neddylation. This study identifies a previously unappreciated enzymatic function of rapsyn and a role of neddylation in synapse formation, and reveals a potential target of therapeutic intervention for relevant neurological disorders.

rapsyn, AChR, RING domain, neddylation, E3 ligase

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.

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Dec 5, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

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.

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