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Yale researchers visualize “ultra-slow” axonal transport in a living organism

September 27, 2023
by Pauline Charbogne

Neurons have very long and thin axons. To protect them and prevent axon breakage, a cellular skeleton is necessary. Most proteins, including cytoskeletal proteins, are synthesized in the cell body, and then need to be transported along the axon, which can be up to a meter away in human. And to travel this distance, it can take weeks or months.

Neurons contain lots of different components that have very specific positions. Although we know where those components are, we don't know how they get there. What we discovered is how one very important component, called the membrane periodic cytoskeleton, ends up where it needs to be....

Grace Swaim, graduate student in Yale’s Cell Biology Program and co-first author of the study

The team focused on spectrin, a protein that is a major component of the membrane periodic cytoskeleton. Spectrin forms a large scaffold that occupies the entire membrane of the axon. Because spectrin is everywhere in the axon and its transport is very slow, it is technically challenging to tell apart what is currently being transported very slowly and what is staying in place.

We were able to develop a method that allowed us to follow this slow transport route

Oliver Glomb, PhD, postdoctoral fellow in Shaul Yogev’s lab and co-first author of the study

In a new study published on September 25 in Developmental Cell, a collaborative team of Yale researchers was able to visualize, for the first time in a living organism, the speed at which spectrin is delivered to the axon. The team’s technical innovation was to label only newly synthesized spectrin: the freshly made spectrin molecules appeared fluorescent under a microscope, while the ones already present in the axon were not visible. With less fluorescence visible overall, it became easier to follow the journey of a particular spectrin molecule to its destination.

Glomb and Swaim captured the fluorescence of newly synthesized spectrin in live C. elegans worms over time using a high-resolution microscope, and revealed two distinct mechanisms of spectrin transport: a slow “stop-and-go” (fast then pause) mechanism, and a steady and 100-fold slower “ultra-slow” mechanism. The team is the first one to observe ultra-slow transport in vivo.

The exact reason for the existence of two distinct velocities is unknown, but the team has a hypothesis. “Why some spectrin transport might be so slow is because those spectrin proteins don't only function at a certain destination, but they function along the entire axon” said Glomb.

“It is very important to better understand spectrin transport. We need this transport in order to prevent degeneration of the neuron” said Swaim. “Better basic understanding of this transport route might help understand what happens in neurodegenerative diseases” added Glomb.

The findings were published in September 25 in the journal Developmental Cell. The study is the first to look at dynamics of spectrin axonal transport in vivo. Oliver Glomb, PhD, and Grace Swaim are co-first authors of the study, and Shaul Yogev, PhD, assistant professor of Neuroscience and Cell Biology, is senior author of the study.

Submitted by Pauline Charbogne on September 27, 2023