Neurons die en masse when the spinal cord is injured or when a
person suffers a stroke. Researchers of the Max Delbrueck Center for
Molecular Medicine (MDC) Berlin-Buch, Germany, and of Aarhus
University, Denmark, have unraveled the molecular mechanism which
causes the death not only of damaged neurons, but also of healthy
nerve cells.
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.
Perfect Targets
Dr. Willnow is convinced that proNGF and sortilin are perfect targets
for drug development. "If the receptor sortilin can be blocked by a drug
to prevent proNGF from binding to it, patients with spinal cord injuries
can be treated and damage to neuronal tissue can be reduced," he
says.
Researchers assume that proNGF also induces neuronal cell death in
diseases such as stroke,
Multiple Sclerosis, Alzheimer's and
Parkinson's disease. "However, there is no 'proof of principle' in a
mouse model as yet. That is, we cannot tell if blocking sortilin reduces
neuronal cell death in these diseases, too. We are working on this
problem, but it still may take a while to find the right answer," Dr.
Willnow adds.
The research Dr. Willnow and Dr. Nykjaer now present in Nature
Neuroscience is the result of a relatively short research period. It was
not until 2001 that researchers in the US identified proNGF as the
cause of neuronal cell death. At that time, the mechanism was still
unknown. Only a few years later, in 2004, Dr. Willnow and Dr. Nykjaer
were able to demonstrate that proNGF causes neuronal cell death by
binding to sortilin.
*Roles for the pro-neurotrophin receptor sortilin in neuronal
development, aging and brain injury
Pernille Jansen1, Klaus Giehl1,2, Jens R. Nyengaard3, Kenneth
Teng4, Oleg Lioubinski5, Susanne S. Sjoegaard1, Tilman Breiderhoff5,
Michael Gotthardt5, Fuyu Lin1, Andreas Eilers5, Claus M. Petersen1,
Gary R. Lewin5, Barbara L. Hempstead4, Thomas E. Willnow5,* and
Anders Nykjaer1,*.
1. MIND Center, Department of Medical Biochemistry, Aarhus
University, Denmark;
2. Southwestern Medical Center, Dallas, TX, USA;
3. MIND Center, Stereology and Electron
Microscopy Research Laboratory, Aarhus University, Denmark;
4. Weill Medical College of Cornell University, New York, NY, USA;
5. Max Delbrueck Center for Molecular Medicine,
Berlin, Germany.
