Proteasomes May Be Key to Sensory Signals

Summary: Researchers discovered a novel role of the proteasome, traditionally known as the cell’s waste processor, in nerve cells. Their findings reveal that proteasomes in dorsal root ganglion neurons may act more like signal messengers, aiding in the differentiation between pain and itch sensations.

By blocking proteasomes with specific inhibitors in mice, the researchers observed significant changes in sensory response, highlighting the proteasomes’ role in environmental sensing and neuronal communication. This study not only redefines our understanding of proteasome functions but also opens new avenues for treating sensory disorders.

Key Facts:

1. Proteasomes are traditionally viewed as cellular garbage disposals but are now seen as crucial for signaling in sensory neurons.
2. The study used a proteasome-blocking drug to demonstrate that these structures are essential for normal sensory functions, affecting how quickly mice responded to sensory tests.
3. Researchers suggest that manipulating neuronal membrane proteasomes could potentially alter pain and itch sensations, providing a new target for therapeutic interventions.

Source: Johns Hopkins Medicine

The typical job of the proteasome, the garbage disposal of the cell, is to grind down proteins into smaller bits and recycle some of those bits and parts. That’s still the case, for the most part, but, Johns Hopkins Medicine researchers, studying nerve cells grown in the lab and mice, say that the proteasome’s role may go well beyond that.

Its additional role, say the researchers, may shift from trash sorter to signal messenger in dorsal root ganglion neurons — cells that convey sensory signals from nerve cells close to the skin to the central nervous system.

Results of their experiments, published April 12 in Cell Reports, show that proteasomes may help those specialized neurons sense the surrounding environment, send signals to each other and potentially differentiate between sensing pain and itch, a finding that could help scientists better understand these sensory processes and new targets for treating pain and other sensory problems.

“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,” says Seth S. Margolis, Ph.D., associate professor of biological chemistry at the Johns Hopkins University School of Medicine.

“Proteasomes in the membrane of neurons may help the cells fine tune this messaging process.”

“Proteasomes are more complicated than they appear,” says Margolis. He and his colleagues first found proteasomes in the plasma membranes of central nervous system neurons in mice in 2017, which they dubbed neuronal membrane proteasomes, and have continued studying how these special proteasomes promote messaging, or crosstalk, among neurons.

At the time, Margolis’ focus was on the central nervous system, encompassing the brain and spinal cord. But later, he collaborated with neurobiologist Eric Villalón Landeros, Ph.D., postdoctoral fellow in Margolis’ laboratory at Johns Hopkins, whose work focuses on the peripheral nervous system, the network of neurons running through the rest of the body, closer to the skin, capturing sensory information from the environment.

Margolis and Villalón Landeros wondered whether proteasomes could be found in peripheral neurons, and if so, what they might do.

Using mouse antibodies that glom on to proteasomes, and other methods, the investigators found the proteasomes on the surface of neurons in the spinal cord, dorsal root ganglia, sciatic nerve and peripheral nerves innervating skin.

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

To understand the proteasome’s function in peripheral sensory neurons, the researchers gave mice biotin-epoxomicin, a cell membrane-impermeable proteasome inhibitor that blocks the function of neuronal membrane proteasomes. Then, they performed classic sensory tests.

The researchers found that the mice that got injections of the proteasome-blocking drug biotin-epoxomicin on one side of the body were between 25% to 50% slower than the other side to respond to sensory tests.

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

The researchers used single cell sequencing technology to determine that membrane proteasomes were expressed in a subpopulation of neurons involved in itch sensation and known to be sensitive to histamine, an immune system compound that launches an animal’s (including human’s) response to allergens.

In laboratory culture dishes, the researchers stimulated both itch-related and non-itch related neurons and blocked their membrane proteasomes with biotin-epoxomicin. This resulted in changes to activity in all of the cells.

“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,” says Margolis.

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

Villalón Landeros and Margolis plan to continue working together to determine how neuronal membrane proteasomes function in sensory neurons and in sensing pain versus itch.

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

Additional scientists who contributed to the research are Samuel Kho, Taylor Church, Anna Brennan, Fulya Türker, Michael Delannoy and Michael Caterina from Johns Hopkins.

Funding: Funding for the research was provided by the National Institutes of Health (F32NS119202, R01 NS110754) and a Merkin Peripheral Neuropathy and Nerve Regeneration Center grant.

About this sensory neuroscience research news

Author: Vanessa Wasta
Source: Johns Hopkins Medicine
Contact: Vanessa Wasta – Johns Hopkins Medicine
Image: The image is credited to Seth Margolis and Eric Villalón Landeros, Johns Hopkins Medicine

Original Research: Open access.
“The nociceptive activity of peripheral sensory neurons is modulated by the neuronal membrane proteasome” by Seth Margolis et al. Cell Reports

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Abstract

The nociceptive activity of peripheral sensory neurons is modulated by the neuronal membrane proteasome

Highlights

• The neuronal membrane proteasome (NMP) is found in peripheral somatosensory neurons
• The NMP selectively localizes to specific types of somatosensory neurons
• The NMP mediates crosstalk between sensory neurons to modulate sensitivity to stimulation
• Inhibition of the NMP reduces sensitivity to mechanical and painful stimuli

Summary

Proteasomes are critical for peripheral nervous system (PNS) function. Here, we investigate mammalian PNS proteasomes and reveal the presence of the neuronal membrane proteasome (NMP).

We show that specific inhibition of the NMP on distal nerve fibers innervating the mouse hind paw leads to reduction in mechanical and pain sensitivity.

Through investigating PNS NMPs, we demonstrate their presence on the somata and proximal and distal axons of a subset of dorsal root ganglion (DRG) neurons. Single-cell RNA sequencing experiments reveal that the NMP-expressing DRGs are primarily MrgprA3⁺ and Cysltr2⁺.

NMP inhibition in DRG cultures leads to cell-autonomous and non-cell-autonomous changes in Ca²⁺ signaling induced by KCl depolarization, αβ-meATP, or the pruritogen histamine.

Taken together, these data support a model whereby NMPs are expressed on a subset of somatosensory DRGs to modulate signaling between neurons of distinct sensory modalities and indicate the NMP as a potential target for controlling pain.