Professor Frank Bradke: Releasing the brakes on spinal cord growth

The drag on growth in the spinal cord release

The spinal cord injury on the track – a working group wants to heal the spinal cord.

A new working group of Prof. Frank Bradke study at the German Center for Neurodegenerative Diseases (DZNE) in Bonn wants, how nerve cells following spinal cord injury can stimulate it to regenerate.
Nerve cells in the central nervous system are surrounded by a myelin sheath. This layer protects the nerve cells, but also prevents their regeneration after injury. It contains a number of molecules that can prevent the regrowth of nerve fibers – “similar to stop signs on the road,” says Bradke. Encounter a stop sign such a nerve fiber grows, it no further. Worldwide, scientists are working to identify these growth-inhibiting molecules. Bradke but has taken a different approach: With his team of researchers focused on the nerve cells themselves why they adhere to the stop signs? Can you get the nerve cells to ignore stop signs and still easy to grow? “We are trying to say, nerve cells to make something draufgängerischeren road users,” says Bradke. That this approach is very promising, have proved his previous works already: In animal models, he showed that small amounts of taxol – a drug that is used in cancer therapy – the cytoskeleton of the nerve cells so stable that the severed nerve cells to grow again be encouraged.
Bradkes idea that just might help here Taxol, was preceded by years of research into the development of nerve cells. At an early stage of development begins a nerve cell has a variety of cellular processes of produce. One of these is the axon projections and growing fast. Axons in the spinal cord can be of people up to a meter long, they will forward electrical signals to nerve cells below. All other processes are to dendrites – receive shorter and they are used to input from other nerve cells. During his doctoral work examined Bradke how different the development of the axon from the dendrites and axons, why continue to grow, while initially dendrites during development does not continue to grow first.
A key role was so Bradke, plays the cytoskeleton. In the growth zone at the end of the axon positioned so-called actin bundles. They must be flexible enough so that the axon can grow. The axon itself are microtubules, which give the long processes of nerve cells their structure. In the growth zone must be strong enough to push the actin filaments to the front. Only when microtubule stability and actin filaments are unstable enough, can grow a nerve process. When axons this is the case, not with dendrites. But even after spinal cord injury in the microtubules in axons are broken and unstable – the axons can not grow accordingly. Would it possible, asked Bradke that only by stabilizing the microtubules, the growth capacity of axons is restored? Taxol is a substance which stabilizes microtubules. In fact Bradke and his colleagues were able to show that the addition of small amounts of taxol on the cytoskeleton so affected that a nerve growth is possible. “Taxol has also still the property to prevent scarring. Also facilitates the regeneration of nerve fibers significantly,” says Bradke.
Yet these findings are far from being able to be employed and to help patients, but they give important clues to possible new approaches. A direct influence of the cytoskeleton can promote growth of nerve cells. “Our long-term research can also contribute to neurodegenerative brain diseases such as stroke, Parkinson’s or Alzheimer’s to understand better, because here are damaged nerve cells and axons lose their contacts with downstream cells,” said Bradke.
Frank Bradke studied at the Free University of Berlin and University College London. In 1994 he received his Bachelor of Science degree in Anatomy and Developmental Biology, 1995, the Diploma in biochemistry. During his PhD he worked at the European Molecular Biology Laboratory (EMBL) in Heidelberg. As a postdoc, he moved in 2000 to the University of California, San Francisco and Stanford and was followed by group leader at the Max Planck Institute of Neurobiology, Martinsried. Frank Bradke habilitated in 2009 at the Ludwig Maximilians University of Munich. Since 2011 he is professor and senior group leader of the Working Group Axonal Growth and Regeneration in Neurodegenerative Diseases at Bonn. (Red)

Releasing the brakes on spinal cord growth

Bonn, February 8, 2012. The new working group led by Professor Frank Bradke at the DZNE is studying how nerve cells can be stimulated to regenerate themselves in the case of paraplegia
While broken bones, muscle tears or wounds in the skin usually heal by themselves, the situation is different in the spinal cord. If the spinal cord is severed, it never grows together again. The result is paraplegia. Yet why doesn’t the spinal cord regenerate? And how can people suffering from paraplegia nevertheless be helped? These questions stand at the centre of research being conducted by Professor Frank Bradke and his new working group at the German Centre for Neurodegenerative Diseases (DZNE) in Bonn.
Nerve cells in the central nervous system are surrounded by a myelin sheath. This layer protects the nerve cells but also prevents their regeneration following injuries. It contains a whole series of molecules that may prevent the regrowth of nerve fibres. According to Bradke, these molecules are “comparable to stop signs for road traffic.” If a nerve fibre encounters such a stop sign, it does not grow any further. Scientists around the world are working to identify these growth-inhibiting molecules. Bradke has chosen a different approach, however: he and his working group are focusing on the nerve cells themselves. Why do they stop at the stop signs? Can nerve cells be made to ignore the stop signs and simply continue growing? “We are trying to turn nerve cells into somewhat more reckless drivers,” says Bradke. Bradke’s previous work has already demonstrated that this approach is highly promising: he has shown using animal models that small quantities of Taxol, a substance that is also used in cancer therapy, can stabilise the cytoskeleton of the nerve cells in such a way that severed nerve cells are stimulated to grow again.

Bradke’s discovery that Taxol could help regrow severed nerves was the result of many years of research on nerve cell development. In the early stages of development a nerve cell starts to produce a range of cellular projections. One of these projections becomes the axon and grows rapidly. Axons can be up to one metre long in the spinal cord of humans and they transmit electrical nerve signals to downstream cells. All other projections become dendrites – they are shorter and receive the signals from upstream nerve cells. During his doctoral studies Bradke was already investigating how the development of the axon differs from that of dendrites and why it is that axons continue to grow while dendrites stop growing.
Bradke demonstrated that the cytoskeleton plays a fundamental role in this respect. The growth cone at the end of the axon contains actin bundles. These must be flexible enough so that the axon can grow. The axon itself contains microtubules which give the long projections of the nerve cells their structure. In the growth cone these must be stable enough to push the actin filaments forwards. A nerve projection can only grow when the microtubules are stable enough and the actin filaments are unstable enough. This is the case in axons but not in dendrites. Following an injury to the spinal cord, microtubules in the axons are destroyed and become unstable – the axon can therefore no longer grow. Would it be possible, asked Bradke, to restore the ability of axons to grow simply by stabilising the microtubules? Taxol is a substance that stabilises microtubules. Bradke and his colleagues showed that administering small quantities of Taxol induced nerve growth. “Taxol also has another property: it prevents the formation of scars. This makes the regeneration of the nerve fibres considerably easier,” says Bradke.

These research results are still a long way from practical implementation in clinical settings, but they do give important suggestions for new directions in research. Treatments that directly affect the cytoskeleton can boost the growth of nerve cells. “In the long term our research can also contribute to a better understanding of neurodegenerative diseases of the brain such as stroke, Parkinson and Alzheimer’s Disease, because nerve cells are also damaged in these diseases and axons lose their contacts with downstream cells,” Bradke says.

Frank Bradke studied at Freie Universität Berlin and at University College London. In 1994 he received a Bachelor of Science in Anatomy and Developmental Biology and in 1995 he received his Diploma in Biochemistry. During his doctoral work he conducted research at the European Molecular Biology Laboratory (EMBL) in Heidelberg. He took up postdoctoral positions at the University of California, San Francisco, and Stanford in 2000 and then became the head of the Neurobiology Working Group at the Max Plank Institute in Martinsried. In 2009 Frank Bradke received his venia legendi from LMU Munich. Since 2011 he has been a full professor and Senior Research Group Leader of the “Axonal Growth and Regeneration Working Group” at DZNE in Bonn.
The homepage of the workgroup is found here.

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