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Chemical spray paint identifies new proteins in synapse

graffitti-1435214_1280I recently went to meet Alice Ting, PhD, in her new Clark Center lab, not long after her arrival from MIT. Ting came to Stanford with appointments in genetics, biology and, by courtesy, chemistry, and a lab bustling with students working on projects relating to technologies for studying living cells in exacting molecular detail.

Ting told me the inspiration for her recent work originated in frustration. All of the existing methods for imaging what’s happening inside a cell also disrupt the cell, making it difficult to know if what you are seeing is real.

“I wanted a way to image and study specific proteins in live cells without having to fix or permeabilize those cells, or tag proteins with large bulky labels,” she told me.

Ting recently published a paper in Cell that highlights one of several technologies to come out of her quest for more natural ways of imaging or mapping cells.

In this paper, Ting wanted to find all the molecules that are present in the synaptic cleft, the space between where one neuron sends a signal and the other neuron receives it.

“Even though the synaptic cleft is so important, most of what we know about the molecules in there is through very painstaking one by one studies. It's taken decades of research to produce only a partial list of the proteins that reside in this region,” Ting told me. “What we wanted to do was generate an unbiased map of this extremely important cellular region.”

This is a challenging question because it’s not possible to isolate the space and see what’s in there. Ting had previously developed a clever way of essentially directing a protein to a particular location – in this case the synaptic cleft – then triggering it to do the molecular equivalent of spray painting everything nearby. Then she just has to look for anything coated in the molecular spray paint.

She did that and found that about 80-90 percent of the resulting spray-painted molecules were already linked by previous studies to the synapse. The rest were either newly discovered denizens of the synapse or mistakes, she wasn’t sure which.

Ting hasn’t tested all of those mystery molecules, but she did look into about a third of them and all turned up in the synapse when she used other imaging methods. That was a good sign that her technique had identified new synapse residents rather than duds.

Ting and her group then decided to do a deep dive on one of these newly identified molecules to find out more about what it was doing in the synaptic cleft. It turns out that protein may be part of the answer to a long-standing mystery relating to how two different kids of synapses – one that activates the neuron and one that inhibits it – figure out how to send the right signals.

After completing this closer examination on that one molecule, she’s hoping to find what the others do, and collaborate with her new Stanford colleagues to learn more about what’s taking place within our cell’s open spaces.

Previously: Nobelist neuroscientist Tom Südhof still spiraling in on the secrets of the synapse and Vrrrooom, vrrrooom vesicles: A Stanford researcher’s work on neurotransmission
Image by Elionas

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