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Proteasomes in brain cells play key role in sensing pain

In every cell, a complex called the proteasome acts like a recycling center, breaking down unneeded proteins. However, recent discoveries by Johns Hopkins Medicine suggest these proteasomes are more than just cellular custodians – they’re also crucial communicators in the nervous system.

Proteasomes in neurons

Study co-author Dr. Seth S. Margolis is an associate professor of biological chemistry at the Johns Hopkins University School of Medicine.

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,” said Dr. Margolis. “Proteasomes in the membrane of neurons may help the cells fine-tune this messaging process.”

Sensory information, from temperature changes to touch and potential irritants, constantly bombards skin cells. Proteasomes within these cells may influence how this information is processed and relayed to the nervous system.

This is significant because it opens doors to entirely new avenues of research on pain, itch, and other sensory experiences. If we can understand how proteasomes contribute to this communication process, we might be able to develop therapies that target these cellular mechanisms to alleviate pain or control itch.

Disabling proteasomes in mice

To understand the potential role of proteasomes within the nerves near the skin, the scientists conducted a carefully designed experiment. Their approach centered on temporarily disabling proteasome function in mice.

The experts utilized a specialized drug called biotin-epoxomicin, known to specifically stop proteasomes from doing their usual “clean-up” work. Once the proteasomes were blocked, the researchers performed a series of well-established sensory tests on the mice.

The results were striking. Mice that received the proteasome-blocking drug showed a significant delay in their response to sensory stimuli. In fact, their reactions were on average 25 to 50 percent slower than what would be considered normal.

This compelling observation was not mere chance. It strongly suggested a deeper role for proteasomes. While crucial for cellular maintenance, proteasomes also critically influence how nerves near the skin process environmental information.

This breakthrough discovery has the potential to pave the way for entirely new approaches to understanding and managing pain, itch, and other sensations.

Potential key for itch relief

The next step was even more fascinating. The researchers discovered that proteasomes seemed to be around a specific group of neurons connected to the sensation of itch. (Ever wondered why you have an uncontrollable urge to scratch sometimes?) These itch-related neurons are triggered by histamine, a chemical your immune system releases in response to allergens.

The scientists exposed itch neurons in a petri dish to a proteasome-blocking drug. Interestingly, this exposure changed the activity of neighboring neurons. These changes occurred even in neurons that did not detect itch.

“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,” explained Dr. Margolis.

Proteasomes and targeted treatments

The most exciting aspect of this discovery lies in its potential for revolutionizing how we treat sensory conditions. Existing medications known as proteasome inhibitors are already used in the fight against certain types of cancer.

This breakthrough discovery opens up a fascinating new possibility: could we utilize similar medications to directly target the root cause of itch, pain, and related sensory experiences?

By understanding how to precisely manipulate these cellular messengers, scientists may be able to develop treatments that offer relief in a way that current medications cannot. This could be a game-changer, particularly for those who suffer from chronic pain or debilitating itch.

Instead of merely masking symptoms, these new therapies might offer a solution that targets the underlying communication processes within our nervous system.

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

Study significance

This discovery serves as a powerful reminder of the astonishing complexity woven into the very fabric of our existence. Even within the confines of a single cell, a structure so minuscule as to be invisible to the naked eye, we find systems that profoundly influence our daily lives.

The proteasome, once viewed as a mere component of cellular housekeeping, emerges as a potential key player in how we perceive and interact with our environment.

This underscores the profound interconnectedness of biological systems. Seemingly insignificant components may hold the secrets to unlocking a deeper understanding of our bodies, our senses, and ultimately, our place within the intricate tapestry of life itself.

More about proteasomes

Proteasomes are fascinating and complex protein complexes essential to the functioning of cells. They act as a sort of waste disposal system for proteins, ensuring that damaged, misfolded, or no longer needed proteins are promptly broken down and recycled. Here’s a deeper look into their role and importance beyond the specific study we discussed:

Essential role in cellular function

Proteasomes are primarily known for their role in the ubiquitin-proteasome system (UPS). UPS is crucial for maintaining cellular homeostasis. Ubiquitin, a small protein, tags proteins destined for degradation, signaling the proteasome to degrade the tagged protein. This process helps regulate the concentration of particular proteins in cells, crucial for controlling various biological pathways.

Involvement in disease

Several diseases are linked to the malfunctioning of proteasomes. For instance, inadequate proteasome function can contribute to the development of neurodegenerative diseases like Parkinson’s and Alzheimer’s, where proteins aggregate abnormally in cells.

In cancer, proteasomes are often overactive, leading to the excessive degradation of proteins that suppress tumors, thus promoting cancer cell survival and growth. This has led to the development of proteasome inhibitors as cancer treatments.

Role in immune response

Proteasomes also play a vital role in the immune system. They help generate peptides presented on the cell surface to the immune system, a process crucial for immune surveillance. This allows the immune system to recognize and destroy infected or cancerous cells.

Some specialized forms of proteasomes, such as immunoproteasomes, are highly active in immune cells and help in managing immune responses.

Research and therapeutic potential

Research on proteasomes continues to reveal their complexity and versatility in various cellular processes. This research not only deepens our understanding of cell biology but also aids in the development of new therapeutic strategies.

Ongoing research is essential as it continues to uncover new roles and therapeutic potentials of proteasomes in human health and disease.

The study is published in the journal Cell Reports.


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