Researchers highlight the role that “workhorse protein” plays in the proper functioning of the nervous system

A team of researchers from the University of Massachusetts Amherst is the first to show how proteins called “chaperones” are essential to ensuring that neurons can transmit signals to each other. When this neurotransmission breaks down, devastating diseases such as Alzheimer’s disease and Parkinson’s disease, as well as many others, can occur. The team’s research provides insight into how the most crucial part of the process works and provides a stepping stone toward understanding the underlying mechanisms of neurodegenerative diseases.

The research, published recently in the Journal of Biological Chemistryhighlights the role that the major chaperone, Hsc70, and a specialized co-chaperone partner, CSPa, play in preparing another highly complex protein, SNAP-25, for its critical role in the machinery responsible for transmission of signals between neurons.

Neurons are specialized cells in the human nervous system, and their job is to transmit the electrical signals that encode the information that allows us to read, think, breathe, eat… in fact, that allows us to do anything What. Although one might be tempted to think of them as electrical wires, this is not correct, because there is a small space, called a synapse, that separates each neuron from its partner.

How an electrical signal passes through this synaptic space is not yet fully understood, but the basic process appears to go like this: a presynaptic neuron receives a message that it has information to transmit, and then the synaptic vesicle at inside that neuron – think of it as a little bucket full of information-rich neurotransmitters being released into the synaptic cleft.

To do this, the synaptic vesicle must anchor to the membrane of the presynaptic neuron and dump its contents into the synapse, where it travels to particular receptors on the postsynaptic neuron. In this way, the neurotransmitter material transfers a signal to the new neuron. This entire process takes just a millisecond, happens millions of times a day, and must be precise.

But all the steps and elements that contribute to it aren’t yet well understood — and that’s where Karishma Bhasne, lead author of the new study and principal investigator at UMass Amherst, comes in.

“I work on a specific protein called SNAP-25,” says Bhasne. “Without SNAP-25, the SNARE complex, responsible for guiding the synaptic vesicle to the correct anchor points on presynaptic neurons, functions poorly.”

SNAP-25 is known as a “disordered” protein, meaning its structure is unstable. It can take many forms and work with many other proteins for a wide variety of tasks. Such flexibility is important for its ability to operate the SNARE complex, but it is also a potential weakness: SNAP-25 can become distracted and stray from its task of helping neurons function.

To understand why SNAP-25 is rarely distracted and time generally performs its task perfectly millions of times a day, Bhasne teamed up with Lila Gierasch, professor emeritus of biochemistry, molecular biology and chemistry at the ‘UMass Amherst, the lead author of the article. Gierasch is one of the leading experts in the field of so-called protein “chaperones”: specific proteins whose role is to ensure that other proteins do not get distracted and do their job faithfully. . In particular, Gierasch has long focused his research on the chaperone known as Hsc70.

Together, Bhasne and Gierasch, along with Antonia Bogoian-Mullen, an undergraduate student at UMass Amherst, and Eugenia M. Clerico, a research associate professor of biochemistry and molecular biology at UMass Amherst, wondered: Hsc70, which is still present in our corps and responsible for a wide range of support tasks, keeping SNAP-25 on mission? Previous work by Sreeganga Chandra of Yale University suggested that this was the case, but the story was not explored further.

To uncover the role of Hsc70, Bhasne and co-authors developed a series of experiments that revealed, first, that in the presence of Hsc70 and an assisting co-chaperone, CSPa, SNAP-25 takes up and remains in the right state to work with other protein partners to form the SNARE complex, which enables neurotransmission.

The team dug deeper and observed that not only does Hsc70 help form SNARE, but it actually combines with SNAP-25 into a protein complex. This complex is what keeps SNAP-25 in the correct form for SNARE.

To determine where exactly Hsc70 binds to SNAP-25 to form the protein complex, the team performed a series of protein modifications to determine that of 206 potential sites where the two could bind, only three have the correct attributes. Of these three, only two seem really involved in the binding process.

Overall, this means that every twitch of your finger, every thought, every heartbeat depends, at its most basic level, on Hsc70 correctly identifying two specific protein targets on SNAP-25, thereby contributing to guarantee that the SNARE complex can complete its action. task of transferring information from one neuron to another. And all of this must happen almost instantly, millions of times every day, for decades.

“SNAP-25 has to be perfectly matched for SNARE to work,” says Gierasch, “and it turns out that SNAP-25 depends on Hsc70, our body’s workhorse.”