Dr Thomas Warner

Dr Warner works at the IoN’s Department of Clinical Neuroscience. Here is his summary of his research into childhood dystonia:

“Childhood onset dystonia is a severe and disabling form of movement disorder characterised by involuntary muscle spasms.

It is most commonly due to a genetic change (mutation) in the DYTI gene. This gene encodes a protein called torsinA, which is found in most cells, especially those in our brain, which are called neurons. Understanding how this gene and protein work in health and in people with dystonia would represent an invaluable step forward into why dystonic movements arise. It may also identify novel treatment strategies with which to tackle this incurable condition.

We have investigated the way in which mutant torsinA causes dystonia in nerve cell models and identified two novel proteins that interact with torsinA, called Snapin and CSN4.

Snapin is involved in the release cycle of the packets of chemical messengers (called synaptic vesicles) which allow our nerve cells to communicate to each other and ultimately make the brain work. We have also found that the normal torsinA protein is involved in regulating this process, a function which is lost by the mutant form.

These findings are of great significance as, for the first time, they provide a link between the mutated DYT1 gene and abnormal nerve cell signalling which leads to dystonic movements.

CSN4 is an important component involved in controlling the breakdown of other proteins. We hypothesise that interaction between torsinA, Snapin and CSN4 is important in regulating this process of synaptic vesicle turnover.

This proposal aims to study how these three proteins interact at a biochemical level, and how the dystonia-associated mutation of torsinA alters this interation.

We will then study in detail the mechanism of protein degradation at the synapse and the process of synaptic vesicle turnover in cultured neurons genetically regulated to express the abnormal form of torsinA and/or in neuronal cells where the total torsinA protein has been stongly reduced and compare this to normal cells. As a result, this integrated programme of experiments will help understand torsinA function(s) in neuronal cells and how the mutated form leads to the development of abnormal movements.”