Powerful new protein treats memory loss and brain injury

Researchers found a powerful protein that helps strengthen the messaging system of the brain. The discovery could lead to new ways of treating diseases that interfere with the way brain cells talk to each other, including Alzheimer's, Parkinson's, and head trauma.

Researchers recently examined how the brain protein cypin controls where other proteins are situated within synapses—the tiny bridges between nerve cells that pass signals. The research, led by Rutgers University-New Brunswick professor Bonnie Firestein, showed that cypin plays a vital role in making synaptic connections stable and efficient, especially during development and even into adulthood.

Cypin has long been a protein of interest to neuroscience researchers. But Firestein's latest research investigates much more extensively than previous research. Her lab found that cypin helps tag a specific molecular address—K63-polyubiquitin—to proteins within the synapse.

These tags act as an address label on a cell, pointing proteins to the right destination so that the neurons can deliver and receive signals. Without this specific targeting, brain cells cannot talk to each other, and this can damage memory, thinking, and overall brain function.

Your neurons rely on highly coordinated interactions to stay linked together. They allow your brain to save information, recall things, and make sense of what you look at, hear, and feel. The synapse is the secret to this communication. It is a thin space where signals are relayed from one neuron to the next. Proteins within the synapse control whether these signals are strong or weak. If proteins get misplaced or break down too quickly, the signals are weakened.

Enter cypin. This protein helps add chains of K63-linked polyubiquitin—a type of molecular tag—to other proteins at the synapse. These tags are not used for destruction (like other tags can be used). Instead, they help direct proteins to the right place, keeping the synapse organized and running smoothly. While K63-polyubiquitination has been studied in cancer biology, what it does in the nervous system was previously unknown.

Firestein's lab showed that cypin boosts this labeling process on both the signal-sending and the signal-receiving side of the synapse. This results in more accurate placement and stabilization of essential synaptic proteins. As brain cells build stronger synapses, they signal more effectively and reliably, solidifying learning and memory.

The study also examined the interaction of cypin with another protein complex called the proteasome. The proteasome acts like a recycling facility, breaking down unnecessary or damaged proteins within the cell. But if it breaks down too much, it is hazardous. The brain needs a balanced amount of protein turnover to function efficiently.

Cypin retards the breakdown process by directly attaching to the proteasome. The greater the amount of cypin, the less protein is broken down. This results in a buildup of certain proteins at the synapse that effectively helps to preserve or enhance communication between neurons. The buildup is not harmful—it appears to render synapses more efficient by giving the neurons more tools to send signals.

This balance is especially important in neurodegenerative disease. In Alzheimer's or Parkinson's, the proteins at the synapse are lost or dysregulated. Firestein's research suggests that by augmenting cypin function, it could be possible to preserve those proteins and preserve synaptic function.

The second discovery from the research was a second protein, UBE4A. It is also a part of the tagging process. Firestein's team found that cypin boosts the activity of UBE4A. By doing this, cypin increases its reach throughout the tagging system, still boosting how proteins are deposited and maintained at synapses.

This suggests cypin does not function alone. It seems to function in the context of a larger system of protein interaction. In improving UBE4A activity, cypin increases the brain's ability to regulate its synaptic proteins. These synergy effects are potentially an important advantage for the treatment of brain disorders where protein positioning is disrupted.

Although the research is still in its infancy, Firestein describes the findings as having real potential for medical use. She and her lab are already seeking "translational" research—efforts to bring laboratory findings into clinical therapies.

"This study is what we call basic research," said Firestein. But eventually it can be applied to real-world, clinical use. That is, training in how cypin-based treatments might restore patients with brain injuries or stop the development of diseases that erode thought and memory.".

The most promising of these possibilities is using cypin to assist synaptic plasticity. This is the ability of synapses to become stronger or weaker depending on activity. Plasticity of synapses is what is behind learning and adapting. Alzheimer's and various other diseases tend to reduce this flexibility, which makes the brain struggle more to adapt. Since cypin helps maintain the strength and position of synapses, it may also help recover plasticity.

Firestein's research suggests that increasing levels of cypin, or improving its capacity to label and protect proteins, could restore or stabilize dysfunctional synapses. This could enhance the outlook for those with traumatic brain injury, or with early stages of neurodegenerative disease.

While the new finding sheds light on how cypin works, much is still mysterious. How exactly does cypin know which proteins to target? Can there be harm in stimulating cypin activity too high? Could cypin therapies be added to existing treatments for Alzheimer's or Parkinson's?

Future scientists will examine these questions. Firestein and colleagues plan to examine cypin's role in intact brain tissue and see how it behaves under diseased conditions. They will examine how boosting cypin impacts the brain long-term.

This research holds the solution to creating therapies that strengthen the communication system of the brain from within. If cypin can keep synapses healthy, it might hold the secret to a fundamental aspect of fighting against cognitive decline and brain trauma.

Research findings are available online in the journal Science Advances.

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