In animal experiments, they have now been able to demonstrate that neuronal cell death can be reduced when the gene of one the key players in this process is knocked out. The research results of Professor Thomas E. Willnow (MDC) and Professor Anders Nykjaer (Aarhus University) have been published online in Nature Neuroscience (DOI: 10.1038/nn2000)*. Now they are working on the development of drugs to limit neuronal cell death after spinal cord injury.

After injury, neurons secrete the precursor protein proNGF. (The abbreviation stands for pro-nerve growth factor). ProNGF binds to a receptor called sortilin, situated on the surface of all neurons whether they are injured or not.

As soon as proNGF binds to sortilin, it induces the lethal cascade. This explains why proNGF not only promotes the death of damaged neurons, but also of the surrounding healthy tissue.

In the embryo, inducing death of neurons is an absolutely necessary process. It keeps the developing nervous system under control. For the adult organism, however, this deadly activity is disastrous.

It not only causes the massive death of injured neurons, but also kills the healthy nerve cells. This shows that neurons not only die because of the initial insult, such as lack of oxygen in stroke. To a large extent, nerve cells also die as a consequence of proNGF ™s binding to sortilin, Dr. Willnow explains.

With a technology for which three scientists in the US and UK have just won the Nobel Prize, Dr. Willnow and Dr. Nykjaer bred mice in which they silenced the gene for sortilin. They could show that in knock-out mice lacking sortilin, most neurons survive spinal cord injury. By contrast, in mice still expressing sortilin on the surface, up to 40 percent of the affected nerve cells are lost.

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To find out if the droopy-tailed fish were asleep, Yokogawa checked to see if they experienced sleep rebound, the drive to try to catch up on lost sleep, after being sleep-deprived. So first he had to make sure the fish stayed awake. Tapping on the aquarium walls and using an underwater speaker didn't work, but he found a gentle electrical pulse kept fish active. He then created a computerized system to stimulate a fish each time it started to doze off. Once a sleep-deprived fish returned to a peaceful, dark aquarium, it compensated for lost rest with longer napping.

Unfortunately, some of the researchers had to stay awake along with the fish. "Originally, we didn't have the automated sleep-deprivation system, so I manually sleep-deprived them, becoming sleep-deprived myself," Yokogawa added.

The new model has already provided insights into the function of sleep-regulating molecules and brain circuits in zebrafish. Compared with normal zebrafish, the sleep mutants with neurons lacking hypocretin receptors experienced something akin to insomnia rather than narcolepsy. Although in dogs the loss of the receptor results in full narcolepsy, in zebrafish only nighttime activity was affected. Overall sleep decreased 30 percent in mutant fish, and when they finally did drift off, they remained asleep only half as long as normal fish.

Future research will search for fish mutants that might oversleep or lack sleep completely, in hopes of discovering new regulatory molecules and brain networks passed on through evolution to humans. "Many people ask the questions, 'Why are we sleeping?' and, 'What is the function of sleep?'" Mignot said. "I think it is more important to figure out first how the brain produces and regulates sleep. This will likely give us important clues on how and maybe why sleep has been selected by natural evolution and is so universal."

The Howard Hughes Medical Institute and the McKnight Foundation funded the study. The other authors are graduate students Wilfredo Marin, Jian Zhang, Guillaume P?©zeron; research associate Juiette Faraco, PhD; postdoctoral scholar Lior Applebaum, PhD; and professor Fr?©d?©ric Rosa, PhD, at the Ecole Normale Sup?©rieure in Paris.

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