Expanding the role beyond cellular waste management

The typical job of the proteasome, the cell's garbage disposal, is to grind proteins into smaller pieces and recycle some of those pieces or parts. For the most part, that's still the case, but Johns Hopkins University Medical researchers studying neuronal cells and mice grown in the lab say the proteasome's role may go far beyond that. There is.

According to the researchers, its additional role could shift from trash sorter to signal transducer in dorsal root ganglion neurons. Cells that transmit sensory signals from nerve cells near the skin to the central nervous system.

The results of their experiment were published on April 12th. cell reporthave shown that proteasomes may help specialized neurons sense their environment, send signals to each other, and differentiate between pain and itch sensations, a finding that scientists hope will help these It could help us better understand sensory processes in the brain and new targets for treating pain and other sensory problems.

Neurons have lived next to each other for a long time and need a way to communicate with each other about what they're doing and who they are. Proteasomes, located in the membranes of neurons, may help cells fine-tune this messaging process. ”

Dr. Seth S. Margolis, Associate Professor of Biochemistry, Johns Hopkins University School of Medicine

“The proteasome is more complex than it appears,” Margolis says. He and his colleagues first discovered proteasomes in the plasma membrane of mouse central nervous system neurons in 2017, naming them neuronal membrane proteasomes, and discovered how these specialized proteasomes play a role in messaging between neurons, i.e. I have continued to research whether it promotes crosstalk.

At the time, Margolis focused on the central nervous system, which includes the brain and spinal cord. But then he collaborated with neurobiologist Eric Villalon Landeros, Ph.D., a postdoctoral fellow in the Margolis lab at Johns Hopkins University, whose research focused on the peripheral nervous system, which runs through the rest of the body. It focuses on networks of neurons. The skin acquires sensory information from the environment.

Margolis and Villalon Landeros wondered whether proteasomes might exist in peripheral neurons, and if so, what happens.

Using mouse antibodies that recognize proteasomes and other methods, researchers found proteasomes on the surface of neurons in the spinal cord, dorsal root ganglia, sciatic nerve, and peripheral nerves that innervate the skin.

The researchers were also able to find proteasomes in the same type of peripheral neurons grown in laboratory dishes.

To understand the function of proteasomes in peripheral sensory neurons, the researchers treated mice with biotin-epoxomicin, a membrane-impermeable proteasome inhibitor that blocks the function of nerve membrane proteasomes. Next, we conducted a classic sensory test.

The researchers found that mice injected with the proteasome inhibitor biotin-epoxomycin on one side of their bodies responded 25 to 50 percent slower on sensory tests than on the other side.

“This suggests that membrane proteasomes are important for sensation, and must be facilitating this at a signaling level,” Margolis says.

Using single-cell sequencing technology, researchers found that membrane proteasomes are sensitive to histamine, an immune system compound that is involved in the sensation of itch and initiates responses in animals (including humans) to allergens. We confirmed that it is expressed in a subpopulation of neurons known to be

The researchers stimulated both itch-related and non-itch-related neurons in laboratory dishes and blocked their membrane proteasomes with biotin-epoxomycin. This caused changes in the activity of all cells. “Blocking the proteasome appears to have an activity-modulating effect across all cells, even though it is expressed in a subpopulation. This suggests that the proteasome facilitates a kind of crosstalk between these cells. ,” Margolis said.

Proteasome blockers, including one called Velcade, are currently used to treat certain types of cancer.

Villalón Landeros and Margolis plan to continue collaborating to understand how neural membrane proteasomes function in sensory neurons and in the sensing of pain and itch. “We want to see if we can manipulate the neural membrane proteasome to produce different outcomes for pain and itch,” says Villalon Landeros.

Other scientists who contributed to the study are Samuel Coe, Taylor Church, Anna Brennan, Fruya Turker, Michael Delanoy, and Michael Caterina of Johns Hopkins University.

Funding for this study was provided by grants from the National Institutes of Health (F32NS119202, R01 NS110754) and the Markin Center for Peripheral Neuropathy and Nerve Regeneration.