The Roots of Cockayne Syndrome Revealed

An approved drug used to treat depression and pain, called amitriptyline, can provoke brain cell development in the lab. The finding has helped a University of Toronto researcher 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.

“It was rewarding to add our pharmacology perspective to stem cell research,” says Rebecca Laposa, an assistant professor in the Department of Pharmacology and Toxicology, who participated in the research along with lead researchers from the British-based Francis Crick Institute. “This research using a pharmacological approach to interrogate and modify disease biology is an exciting example of the translational research happening at U of T.”

To learn more about the basic mechanisms of the disease, the team 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. The researchers may have found a way around this problem.

The research, published in Cell Reports on March 10, shows how cells can bypass the need for CSB protein and still make neurons. The researchers 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 to 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 were able to form neurons.

Amitriptyline is approved by the FDA to treat depression and pain, but it’s unknown how well the medication will perform in individuals living with CS. So far, the treatment has only been tried in isolated cells in a lab.

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