The crucial role of 'chaperones' in maintaining neuronal function

A team of researchers from the University of Massachusetts Amherst is the first to show how proteins called "chaperones" are vital in ensuring that neurons can transmit signals to one another. When this neurotransmission breaks down, devastating diseases such as Alzheimer's and Parkinson's along with many others, can occur.

The team's research provides a new understanding of how the most crucial part of the process works and is a stepping stone toward understanding the underlying mechanics of neurodegenerative diseases.

The research, published recently in the Journal of Biological Chemistry, highlights the role that the major chaperone, Hsc70, and a specialized partner co-chaperone, CSPa, play in preparing another highly complex protein, SNAP-25, for its critical role in the machinery responsible for transmitting 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 … really, that allows us to do anything. While one might be tempted to envision them as electrical wires, that's not correct, because there is a small gap -; called the synapse -; that separates every neuron from its partner.

How an electrical signal crosses that synaptic gap is not yet entirely understood, but the basic process seems to go like this: a presynaptic neuron receives a message that it has information to transmit, and then the synaptic vesicle within this neuron -; thinks of it as a small bucket full of information-rich neurotransmitter material -; is released into the synaptic gap.

To do this, the synaptic vesicle must dock at the membrane of the presynaptic neuron and dump its content into the synapse, where it moves to particular receptors on the postsynaptic neuron. In this way, the neurotransmitter material transfers a signal to the new neuron. This entire process takes only a millisecond, happens millions of times a day -; and it has to be precise.

But all the steps and all the pieces that make it happen are not yet well understood -; and this is where comes in.  I work on a specific protein called SNAP-25. Without SNAP-25, the SNARE complex, which is responsible for guiding the synaptic vesicle to the right docking points on the presynaptic neurons, malfunctions."

Karishma Bhasne, Study Lead Author and Senior Research Fellow, University of Massachusetts Amherst

SNAP-25 is known as a "disordered" protein, which means that its structure is unstable. It can take many forms and work with many other proteins on a wide variety of tasks. Such flexibility is important for its ability to make the SNARE complex work, but it's also a potential weakness: SNAP-25 can get distracted and wander off from the job of helping neurons work.

To understand why SNAP-25 only rarely gets distracted and usually time performs its task flawlessly millions of times a day, Bhasne teamed up with Lila Gierasch, Distinguished Professor of Biochemistry and Molecular Biology and Chemistry at UMass Amherst, the paper's senior author. Gierasch is one of the foremost experts on what is known as protein "chaperones": specific proteins whose job is to make sure that other proteins don't get distracted and do their jobs faithfully.

In particular, Gierasch has long focused her research on the chaperone known as Hsc70. Together, Bhasne and Gierasch, along with UMass Amherst undergraduate Antonia Bogoian-Mullen and Eugenia M. Clerico, UMass Amherst research associate professor of biochemistry and molecular biology, wondered: could Hsc70, which is ever-present in our bodies and responsible for a wide-range of chaperoning tasks, be keeping SNAP-25 on task? There were hints that this was the case from previous work done by Yale University's Sreeganga Chandra, but the story was not fleshed out.

To uncover Hsc70's role, Bhasne and her co-authors crafted a series of experiments which found, first, that in the presence of Hsc70 and a helper co-chaperone, CSPa, SNAP-25 takes on and remains in the proper state to work with other protein partners to form the SNARE complex-; which enables neurotransmission.

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

To figure out where, exactly, Hsc70 binds with SNAP-25 to form the protein complex, the team performed a series of protein edits to determine that out of 206 potential sites where the two could bind, only three have the correct attributes. Of those three, only two seem to be actually involved in the binding process.

Put all together, 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, thus helping to ensure that the SNARE complex can complete its task of transferring information from one neuron to another. And all of this needs to happen nearly instantaneously, millions of times every day, for decades on end.

"SNAP-25 has to be exactly right for SNARE to work," says Gierasch, "and it turns out that SNAP-25 depends on Hsc70, the workhorse of our bodies."