In order to be able to walk and eat and function, the brain needs to be able to transmit strong signals to our muscles. Now scientists from Georgia Health Sciences University’s Medical College have discovered that to ensure a robust conversation between brain and muscles, a protein called LRP4, which is located in muscle cells and neurons needs to be present.
The study, published in the journal Neuron, shows that without the presence of LRP4, the communication between the two cells types is inefficient and short-lived.
Abnormalities or lacking proteins seems to be contributor in disabling disorders, including myasthenia gravis, as well as other forms of muscular dystrophy. In a study published earlier this year in Archives of Neurology, MCG scientists reported that 2% of patients with muscle-degenerating myasthenia gravis had antibodies to LRP4 in their blood.
Study author, Dr. Lin Mei, Director of the GHSU Institute of Molecular Medicine and Genetics said that scientists are aware of the fact that the impact of LRP4 on the muscle cells is important. The brain cell sends a signal to the LRP4 to induce the formation of receptors that allow an ongoing communication between the brain and the muscle cells.
Dr. Haitao Wu observed that when LPR4 was deleted just from muscle cells, the connection, although weak, was still established between both cells. Wu noted that the mice survived several days, but that they experienced muscle weakness similar to patients with myasthenia gravis. Mei, who is also a Georgia Research Alliance Eminent Scholar in Neuroscience, declared: “That’s against the dogma. If LRP4 is essential only in the muscle cells, how could the mice survive?” They discovered that a total elimination of LRP4 resulted in death because neuromuscular junctions never formed.
Wu says that additional evidence indicates the necessity of LRP4 in the neurons in order to survive. Wu explains: “When we knocked out the LRP4 gene in the muscles, there was some redundant function coming from the motor neuron, like a rescue attempt.”
Although they documented the process of the neuron reaching out to share LRP4 with the muscle cell, it proved insufficient.
Mei looked at images of neurons that were too long, which never received the message from the muscles that they have gone far enough, saying: “The nerve does not get the stop signal.” On dissecting the elongated nerves, the team discovered that they did not contain sufficient vesicles, i.e. little packages of chemical messengers that are typical in brain cell communication, whilst the receptors developed by the muscle cells on the receiving end were too small and too few, which explains the weak communication link.
Mei, whose lab established earlier that the communication between brain and muscle cells is a two-way conversation, declared: “When LRP4 in the muscle is taken out, not surprisingly, the muscle has some kind of a problem. What was very surprising was that the motor neurons also have problems.”
Wu added: “The talk between motor neurons and muscle cells is very critical to the synapse formation and the very precise action between the two.”
The researchers hypothesize that around 60% of the LRP4 stems from muscle cells and around 20% from brain cells, with the remainder from cells located in spaces between both. This could explain why the brain’s effort to share is insufficient. Aside from gaining a better insight into the workings of the nerve-muscle communication, the researchers hope their findings will enable gene therapy that delivers LRP4 to bolster insufficient levels in patients in the future.
Another protein that plays an early and major role in establishing nerve-muscle conversation is agrin, which is released by motor neurons to direct construction of the synapse, like a telephone line between the nerve and muscle. Critical internal cell talk is initiated by the MuSK enzyme on the muscle cell surface, which enables formation of synapses and receptors that allow specific commands to cluster at just the right spot.
In 2008, a study at Mei’s lab in Neuron revealed that agrin starts talking with LRP4 on the muscle cell surface and then recruits the enzyme MuSK to join the conversation. LRP4 and MuSK are vital components in order for the muscle cell to be able to receive the message agrin transmits.
Researchers have found that the agrin-MuSK signaling pathway plays a role in muscular dystrophy, various genetic diseases, which lead to loss of muscle control due to problems that involve neurons, muscle cells and/or their communication. According to some studies, a mutant MuSK has been implicated as a cause of muscular dystrophy and auto-antibodies to MuSK in the blood of some patients. Auto-antibodies are formed in response to, and reacting against, an antigenic component of the body’s own tissues.
Written by Petra Rattue