Cell's Garbage Disposal May Also Send Sensory Signals Beyond Recycling

The proteasome, the cell's garbage disposal mechanism, usually breaks down proteins into smaller pieces and recycles some of the pieces.

That is still largely the case, but researchers at Johns Hopkins Medicine suggest that the proteasome may play a much larger role. They are studying both mice and lab-grown nerve cells.

The researchers speculate that its secondary function in dorsal root ganglion neurons, which transmit sensory signals from skin-proximal nerve cells to the central nervous system, may change from trash sorter to signal messenger.

The findings of their studies, which were published on April 12^th, 2024, in Cell Reports, suggest that proteasomes may aid those specialized neurons in detecting their surroundings, exchanging signals with one another, and possibly distinguishing between pain and itching. This discovery may provide new avenues for the treatment of pain and other sensory issues, as well as a deeper understanding of these sensory processes.

Neurons live next to each other for a long time, and they need ways to communicate with each other about what they’re doing and who they are. Proteasomes in the membrane of neurons may help the cells fine tune this messaging process. Proteasomes are more complicated than they appear.”

Seth S. Margolis, Ph.D., Associate Professor, Department of Biological Chemistry, Johns Hopkins University School of Medicine

In 2017, Margolis and colleagues discovered what they called neuronal membrane proteasomes, which are unique proteasomes in the plasma membranes of central nervous system neurons in mice. Since then, they have been investigating how these unique proteasomes facilitate neuronal communication, or crosstalk, among neurons.

At the time, Margolis had been studying the central nervous system, which included the brain and spinal cord. The peripheral nervous system is the network of neurons that runs through the rest of the body, closer to the skin and is responsible for capturing sensory information from the environment. Later on, however, he worked with neurobiologist Eric Villalón Landeros, Ph.D., a postdoctoral fellow in Margolis' laboratory at Johns Hopkins.

Margolis and Villalón Landeros pondered whether peripheral neurons contained proteasomes and, if so, what possible uses they might have.

The researchers discovered proteasomes on the surface of neurons in the spinal cord, dorsal root ganglia, sciatic nerve, and peripheral nerves innervating the skin using mouse antibodies that cling to proteasomes and other techniques.

The researchers discovered proteasomes of the same kind in peripheral neurons cultured in lab culture dishes.

The researchers administered mice biotin-epoxomicin, a cell membrane-impermeable proteasome inhibitor that inhibits the activity of neuronal membrane proteasomes to better understand the role of proteasomes in peripheral sensory neurons. They then conducted traditional sensory examinations.

Researchers discovered that mice receiving injections of the proteasome-blocking medication biotin-epoxomicin on one side of their bodies responded to sensory tests 25%–50% slower than the other side.

This suggests that membrane proteasomes are important for sensation, and they must be facilitating this at the signaling level.”

Seth S. Margolis, Ph.D., Associate Professor, Department of Biological Chemistry, Johns Hopkins University School of Medicine

The researchers discovered that membrane proteasomes were expressed in a subpopulation of neurons involved in itching and known to be sensitive to histamine, an immune system substance that triggers an animal's (including human) body's reaction to allergens. They made this discovery using single-cell sequencing technology.

After stimulating the neurons, the researchers used biotin-epoxomicin to block the membrane proteasomes of both itch-related and non-itch-related neurons in laboratory culture dishes. All of the cells' activities changed as a result.

Margolis said, “Blocking proteasomes seems to have an activity-modulatory effect across all the cells, despite being expressed in a subpopulation, suggesting that proteasomes facilitate a kind of cross-talk between these cells.”

Proteasome blockers, such as Velcade, are used to treat specific cancers.

Villalón Landeros and Margolis intend to conduct more research to ascertain the role of neuronal membrane proteasomes in sensory neurons and distinguish between pain and itching.

We want to see if we can manipulate neuronal membrane proteasomes to have a different outcome on pain and itch sensation.”

Eric Villalón Landeros, Ph.D., Neurobiologist and Postdoctoral Fellow, Johns Hopkins University School of Medicine