Researchers highlight the role ‘workhorse proteins’ play in keeping the nervous system running smoothly

A team of researchers at the University of Massachusetts Amherst has shown for the first time how proteins called “chaperones” are important for allowing neurons to transmit signals to each other. Disruption of this neurotransmission can lead to serious diseases such as Alzheimer’s disease, Parkinson’s disease, and many other diseases. The team’s research provides new understanding of how the most important parts of the process work and is a stepping stone to understanding the mechanisms underlying neurodegenerative diseases.

The study, recently published in the Journal of Biological Chemistry, shows that Hsc70, a major chaperone, and a specialized partner, CSPa, a co-chaperone, are important in the preparation of SNAP-25, another highly complex protein. It emphasizes the role played. A machine responsible for transmitting signals between neurons.

Neurons are specialized cells in the human nervous system whose job is to transmit electrical signals that encode the information that allows us to read, think, breathe, eat… in short. That’s it. You might be tempted to imagine them as electrical wires, but that’s not true. That’s because there is a small gap (called a synapse) that separates every neuron from its partner.

How electrical signals cross synaptic gaps is still not fully understood, but the basic process appears to be as follows. Think of it like this: a presynaptic neuron receives a message that it has information to transmit, and then synaptic vesicles within this neuron. Small buckets filled with information-rich neurotransmitters are released into the synaptic gap.

To do this, synaptic vesicles must dock to the membrane of the presynaptic neuron and dump their contents into the synapse, where they are transferred to specific receptors on the postsynaptic neuron. In this way, neurotransmitters transmit signals to new neurons. This entire process takes just 1 millisecond, runs millions of times a day, and must be accurate.

But all the steps and all the elements to make it happen are still not well understood. That’s where Karishma Bhasne, lead author of the new study and senior research fellow at Amherst College, comes in.

“I’m working on a particular protein called SNAP-25,” Basne says. “In the absence of SNAP-25, the SNARE complex, which is responsible for guiding synaptic vesicles to the correct docking point on the presynaptic neuron, becomes dysfunctional.”

SNAP-25 is known as a “disordered” protein, meaning that its structure is unstable. It takes different forms and works with many other proteins in different tasks. Although such flexibility is important for enabling SNARE’s complex features, it is also a potential weakness. SNAP-25 can be distracting and distract your neurons from their job of helping them work.

To understand why SNAP-25 is rarely distracted and typically performs its mission flawlessly millions of times a day, Basne, the paper’s lead author, We collaborated with Laila Gierash, Distinguished Professor of Biochemistry and Molecular Biology and Chemistry at Amherst State. Geelash is one of the leading experts in what are known as protein “chaperones.” Chaperones are specific proteins whose role is to allow other proteins to faithfully carry out their tasks without distraction. In particular, Gierash has long focused on researching a chaperone known as Hsc70.

Mr. Basne and Mr. Gierash, along with Antonia Bogoin-Mullen, an undergraduate student at the University of Massachusetts Amherst, and Eugenia M. Clerico, an associate professor of biochemistry and molecular biology at the University of Massachusetts Amherst, We thought that there might be Hsc70, which is always present in the body and causes various causes. -You have a variety of escort duties, but do you always use your SNAP-25? There were hints that this might be the case from previous research by Sriganga Chandra at Yale University, but the story was never fleshed out.

To clarify the role of Hsc70, Basne and his co-authors conducted a series of experiments. The results first revealed that in the presence of Hsc70 and its co-auxiliary CSPa, SNAP-25 acts to maintain an appropriate state. Other protein partners form SNARE complexes and enable neurotransmission.

Taking a closer look, the researchers observed that Hsc70 not only helps form SNAREs, but actually binds to SNAP-25 to form a protein complex. This complex keeps SNAP-25 in the correct form of a SNARE.

To elucidate the exact location where Hsc70 binds to SNAP-25 to form a protein complex, the researchers performed a series of protein edits to determine which of the 206 possible sites the two could bind to. , I found that only 3 had the correct attributes. Of these three, only two appear to actually be involved in the binding process.

Taken together, this means that every twitch of a finger, every thought, every heartbeat depends, at the most basic level, on Hsc70, which precisely identifies two specific protein targets on SNAP-25. , ensuring that the SNARE complex can complete its role. The task of transmitting information from one neuron to another. And all of this has to be done almost instantly, millions of times every day, for decades on end.

“For SNARE to work, SNAP-25 needs to be just right, and it turns out that SNAP-25 relies on Hsc70, our body’s mainstay.” says.