Posted - March 2010 in Research Highlights
Mark Weber of the SP Foundation in the US provides this non-technical description of how an important part of the nerves (microtubules) work and how they are affected by gene mutations.
Neurons & Nerves
Cells called upper motor neurons (UMN’s) reside in the brain. Picture the cell body of an UMN as a misshapen sphere.
Every UMN has a tail called an axon. Picture an axon as a tube. Picture the whole UMN as a sphere with a tube sticking out of it. Diagrams and pictures are contained in slides 6, 7 and 8.
An UMN’s axon extends down the spinal cord to where it connects to lower motor neurons (LMN’s). The LMN’s also have axons. Their axons extend out of the spinal cord and ultimately connect to muscle fibers.
The axon of an UMN that controls a leg or foot muscle extends all the way from the brain to the lower part of the spinal cord. It is approximately 60cm long.
Cells & Proteins
Proteins do the work of a cell. In an UMN, the work includes keeping the cell alive and healthy, and communicating with other neurons. All proteins are generated in the ‘cell body’ of a cell. Some proteins are needed in the cell body and others are needed in the axon. Proteins that are needed in the axon travel from an UMN’s cell body in the brain down its axon to wherever they are needed.
Microtubules are long tube-like structures in the axons. They give the axons their shape and provide the axonal protein transportation system. They are also needed to form axonal branches. The more branches in an axon, the more LMN’s an UMN can communicate with.
In order for an axonal branch to be formed, short microtubules are needed. But microtubules are typically long. This is where Spastin comes in. Spastin severs long microtubules into short microtubules as does another protein called Katanin. When there are gene mutations that cause disease, this ability to sever microtubules is impaired.
In his most recent article, Dr. Baas explains how treating cultured UMN’s in a petri dish with a particular growth factor enhances the microtubule cutting actions of both Spastin and Katanin — creating more short microtubules. He goes on to explain how the molecular pathway involved in this process is different for Spastin compared to that of Katanin.
Dr. Baas further discovered that when neurons are created without either Spastin or Katanin, the addition of this growth factor still enhanced microtubule severing – just not as much as when Spastin and Katanin were at the normal levels in the cell.
Just like repairing a car, you can’t fix a neuron unless you know what is wrong with it. Unlike car repairs, scientists are still discovering what all of the parts of a neuron do, and how they function together to cause coordinated movement. Once scientists understand this, they can move on to the next step of fixing what is “broken” in UMN’s that cause HSP and PLS.
The formation of interstitial axonal branches involves the severing of microtubules at sites where new branches form. Here we wished to ascertain whether basic fibroblast growth factor (bFGF) enhances axonal branching through alterations in proteins involved in the severing of microtubules. We found that treatment of cultured hippocampal neurons with bFGF heightens expression of both katanin and spastin, which are proteins that sever microtubules in the axon. In addition, treatment with bFGF enhances phosphorylation of tau at sites expected to cause it to dissociate from microtubules. This is important because tau regulates the access of katanin to the microtubule. In live-cell imaging experiments, axons of neurons treated with bFGF displayed greater numbers of dynamic free ends of microtubules, as well as greater numbers of short mobile microtubules. Entirely similar enhancement of axonal branching, short microtubule transport, and frequency of microtubule ends was observed when spastin was overexpressed in the neurons. Depletion of either katanin or spastin with siRNA diminished but did not eliminate the enhancement in branching elicited by bFGF.
Collectively, these results indicate that bFGF enhances axonal branch formation by augmenting the severing of microtubules through both a spastin-based mode and a katanin-based mode.
Mol Biol Cell. 2010 Jan;21(2):334-44.
Basic fibroblast growth factor elicits formation of interstitial axonal branches via enhanced severing of microtubules.
Qiang L, Yu W, Liu M, Solowska JM, Baas PW.
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA