Safety Catch

Sensations like pain or heat travel in a fraction of a second along the extensions – the axons – of nerve cells, an impressive feat considering that axons such as those that run from the base of the spine all the way down the leg can reach over a meter in length – 40,000 times longer than their width. But when a nerve cell is injured somewhere along its length, a different kind of signal must be sent – one that more closely resembles a mechanical railway car than an electrical impulse. Thus getting the call for help back to the remote cell nucleus is something like sending a message by boxcar to headquarters halfway across the state.

Prof. Michael Fainzilber of the Weizmann Institute’s Biological Chemistry Department has been investigating emergency transportation systems in nerve cells. His previous research had shown that this information is packaged in a molecular “railcar” complex: A motor protein called dynein works together with importins to move the complex along microtubule “tracks.” The importins are nuclear import proteins that ferry various molecules in and out of the nucleus, thus delivering the message straight to the command center of the cell.

Fainzilber and research students Dmitry Yudin and Shlomit Hanz, working in collaboration with the group of Dr. Jeffrey Twiss (Nemours Institute, Wilmington, DE) wanted to know what controls the triggering of this system right after injury, as it gears up for the long journey. Using rat sciatic nerves as their model, the scientists looked for changes in the molecular makeup up of the nerve cell material around the injury site. Their findings recently appeared in Neuron.

To their surprise, they found molecules that until now were believed to exist only around the cell nucleus. These molecules, known collectively as the Ran system, are found in two main configurations, one inside the nucleus and one outside, and they help to control the importins’ molecule-ferrying activities through gates in the walls surrounding the nucleus. The research team found that the nuclear form of Ran sits on the axonal complex, preventing importins from coupling with the rest of the transport machinery. When damage occurs, Ran is switched to the second configuration, which causes it to disengage. The waiting importin can then plug into the machinery, and the expedition gets under way.

The researchers believe the Ran system works like a safety catch – preventing unwanted activation of the alarm machinery until an actual emergency occurs, and then switching quickly to allow efficient triggering of the system. Understanding this mechanism may help devise ways by which nerve cells can be induced to repair damage and may aid in developing treatments for nerve injury in the future.

Prof. Michael Fainzilber’s research is supported by the M.D. Moross Institute for Cancer Research; the Nella and Leon Benoziyo Center for Neurological Diseases; the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; the PW-Bes Foundation; the European Union FP6 NEST Axon Support project; the J&R Center for Scientific Research; the Minerva Foundation; and the USA-Israel Binational Science Foundation. Prof. Fainzilber is the incumbent of the Chaya Professorial Chair for Molecular Neuroscience.