The ability of nerve cells to regenerate relies on a key protein, suggested scientists from Pennsylvania State University in the US, who came across the unexpected discovery when they looked inside severely injured neurons. They hope their finding will help other researchers look for new treatments for nerve disease or damage.

Dr Melissa Rolls, an assistant professor of biochemistry and molecular biology at Penn State, led the study, which appeared online ahead of print on 9 December in the journal Current Biology.

The part of neurons or nerve cells that Rolls and colleagues were investigating when they came across their finding was the dendrites, about which we know very little compared to axons, they said in a press statement.

Neurons are similar to other cells in that they have a a cell body surrounded by a membrane, and which contains a nucleus, cytoplasm, mitochondria and other organelles, and they make protein and energy.

But they differ in how they communicate, and the structures that carry the signals to and from the cell body. They also have to last a lifetime whereas other cells can die off and be replaced.

To communicate, neurons use two types of specialized “arms” called dendrites and axons that project in opposite directions from the cell body.

Axons take information away from the cell body, they have smooth surfaces, and generally there is only one axon per cell. They can be short, and they can be long, and they can branch, but the branches tend to be further away from the cell body.

Dendrites bring information to the cell body, they have rough, spiny surfaces, and there are usually many dendrites per cell and they spread out into several branches quite near the cell body.

Rolls explained that:

“Unlike axons, which form large, easily recognizable bundles, dendrites are highly branched and often buried deep in the nervous system, so they have always been harder to visualize and to study.”

To get around this problem, she and her team used a simple organism, the fruit fly, whose nerve cells are similar to human nerve cells.

They were particularly interested in a nerve cell component called “microtubules”, rigid hollow rods about 25 nm in diameter that undergo continual assembly and disassembly with an agility that would make any Lego enthusiast green with envy.

Although axons and dendrites seem to have more differences than similarities, one key similarity is they both contain these microtubules, that run along their length and do several things like determine cell shape and transport raw materials to and from the far reaches of the cell.

Microtubules, which Rolls described as cell “highways”, have an interesting feature because while they are shaped like cylinders, they are not symmetrical: they have a “plus” end (the growing end) and a “minus” end.

But, and this is where it gets even more interesting: in the axons the microtubules point in a different direction to dendrites.

“In axons, the growing ends — or plus ends — of the microtubules point away from the cell body. In contrast, in the dendrites the plus ends point towards the cell body,” said Rolls.

“No one understands how a single cell can set up two different highway systems,” she added.

Together with their ability to assemble and disassemble quickly, microtubules are also able to grow continuously so they can be rebuilt in response to injury. This gives them the flexibility needed to make them last a lifetime.

Rolls and her team tried to imagine how this growth occurs, and realized there must be a set of proteins controlling how the microtubules are laid out at the key intersections or branch points so they all point in the right direction.

They identified a group of proteins including the motor protein kinesin-2, and showed that when they were missing, the polarity of the microtubules in dendrites became disorganized.

They then set out to find what role these proteins might play when neurons are injured.

They already knew from earlier studies how neurons have an incredible ability to regenerate their missing parts after injury. They had found for example that when you cut off an axon, which effectively denies the nerve cell a way of sending out nerve signals, a new axon grows on the other side of the cell, where the dendrites are.

But what happens to the microtubules when the dendrites grow a new axon? They flip in polarity. In other words, the dendrite “highways” have to be completely disassembled and reassembled to lay down the microtubules the other way around to make an axon.

So what happens when there is no kinesin-2 protein? Rolls and her team discovered that when they disabled the flies’ ability to produce it, the microtubules could not be disassembled and reassembled correctly and nerve regeneration failed.

“Apparently, kinesin-2 is a crucial protein for polarity maintenance and for the ability to set up a new highway system when neurons need to regenerate,” said Rolls.

“We hope that by showing how microtubules are built in healthy neurons and rebuilt in response to injury, our study might provide insights for future researchers who are developing drug therapies for patients with nerve disease or damage,” she added.

“Directed Microtubule Growth, +TIPs, and Kinesin-2 Are Required for Uniform Microtubule Polarity in Dendrites.”
Floyd J. Mattie, Megan M. Stackpole, Michelle C. Stone, Jessie R. Clippard, David A. Rudnick, Yijun Qiu, Juan Tao, Dana L. Allender, Manpreet Parmar, Melissa M. Rolls.
Current Biology, published ahead of print on 09 December 2010.
DOI: 10.1016/j.cub.2010.11.050

Additional sources: Penn State (press release 9 Dec 10); GM Cooper (2000) “The Cell: A Molecular Approach”, 2nd edition, Sinauer Associates, Sunderland MA.

Written by: Catharine Paddock, PhD