Brain cell study reveals root of rare Cockayne Syndrome

10 March 2016

An approved drug used to treat depression and pain, called amitriptyline, can provoke brain cell development in the lab. The finding has helped researchers at the Francis Crick Institute in London to understand more about what causes a devastating hereditary disease called Cockayne syndrome. 

Children diagnosed with Cockayne syndrome (CS) rarely live past their teens. Patients with the condition fail to thrive, have growth problems and age prematurely. There is no cure. The more severe symptoms are caused by problems in brain cell (neuronal) development.

To learn more about the basic mechanisms of the disease, a team led by Dr. Jesper Svejstrup used human cells to look at the network of genes that control how brain cells develop.

To make a brain cell, or neuron, the body needs a protein made by a gene called Cockayne syndrome B (CSB). An immature cell lacking the CSB protein usually can't grow into a fully functioning neuron. Dr. Svejstrup's team may have found a way around this problem.

The research, published in Cell Reports today, shows how cells can bypass the need for CSB protein and still make neurons. The Svejstrup laboratory discovered that a growth booster called brain-derived neurotropic factor (BDNF) made by the brain can guide cells to become neurons even in the absence of CSB. BDNF provides a molecular detour around the roadblock in neurons that lack CSB.

Tissue samples provided by people who lived with CS show they had much less BDNF in their brain cells than usual. This shows that CSB is required for the molecular circuits that keep growth booster levels high.

When the cells were treated with amitriptyline, a drug that mimics some of the major effects of the BDNF molecule, they could go on to form neurons.

Amitriptyline is approved by the FDA to treat depression and pain, but Dr. Svejstrup urges caution in study interpretation: ''We have only been able to look at the effect of this medicine on cells in the lab, not in the much more complex environment of a living person or animal. We can't say that it would help children who have Cockayne syndrome. All drugs have risks and potential benefits associated with them and it would be misleading of us to suggest that these drugs are only useful and not dangerous for CS patients when the research is still at such an early stage."

There is no good mouse model that mimics Cockayne syndrome and so Svejstrup's team have not yet been able to look for the same results in a whole living system.  

In addition to revealing the new route to neuronal development in CS cells, the cell study had another surprise. "Our experiments strongly indicate that at least the neurological aspects of Cockayne syndrome are actually primarily caused by problems with gene regulation, rather than defective DNA repair as previously thought," Dr. Svejstrup explains.  This evidence sets a new focus for future research. 

Several of the study team members were first introduced to each other at a research retreat organized by families of CS patients and their supporters.  The scientists, including a team led by Dr Rebecca Laposa at the University of Toronto and a team led by Dr. Alysson Muotri at the University of California, San Diego, shared both cells and skills to tackle Dr. Svejstrup's complex research problem. Dr. Svejstrup says the families involvement has been crucial: "Here we have a situation where the research overall was strengthened by the contributions and the involvement of CS families. We are all very grateful to the CS families for bringing these researchers closer to each other to accelerate research progress for CS."  

''This research is still at an early stage. We now have a better understanding of what causes Cockayne syndrome at a cellular level. Looking at these basic mechanisms is a first step of many along the journey towards developing a potential treatment for CS. We are still working on it,'' Dr Svejstrup concludes.

Notes to editors:

Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation is published in Cell Reports. 

For more information, please contact:

Francis Crick Institute Press Office

press@crick.ac.uk

The Francis Crick Institute is a new and distinctive biomedical research institute. Its purpose built laboratory in the King's Cross area of London will open in 2016.  The institute's work - which is already underway at the Crick's Clare Hall, Lincoln's Inn Fields and Mill Hill laboratories - will help to understand why disease develops.

We will find new ways to diagnose, prevent and treat a range of illnesses − such as cancer, heart disease and stroke, infections and neurodegenerative diseases. We will bring together outstanding scientists from all disciplines, carrying out research that will help improve the health and quality of people's lives, and keeping the UK at the forefront of medical innovation. The Francis Crick Institute is a charity supported by the Medical Research Council, Cancer Research UK, the Wellcome Trust, UCL (University College London), Imperial College London and King's College London.

  • An approved drug used to treat depression and pain, called amitriptyline, can provoke brain cell development in the lab.
  • The finding has helped researchers at the Francis Crick Institute in London to understand more about what causes a devastating hereditary disease called Cockayne syndrome.