Dystonia – a neurological movement disorder – is estimated to affect around half a million people in the US and Canada alone. For years, researchers have tried to determine what causes the disorder and find ways to prevent and treat it, but to no avail. Now, investigators from the University of Michigan have created a dystonia mouse model that they say could lead to a better understanding of the condition.

The research team, led by Dr. William Dauer, an associate professor in the departments of Neurology and Cell and Developmental Biology at the University of Michigan (U-M), recently detailed their creation in the Journal of Clinical Investigation.

Dystonia is a disorder characterized by involuntary muscle spasms and contractions. Such movements are often repetitive and can sometimes lead to abnormal and painful postures.

There are several forms of dystonia, one type is caused by a mutation in the DYT1 gene and is an inherited form of the disorder. The condition – that typically begins in childhood – usually affects the limbs first before progressing to other areas of the body, causing significant disability.

Progression in dystonia research has been slow, and the researchers believe this is down to lack of a preclinical model of the condition. With this in mind, the U-M team has spent the last 17 years working on a dystonia mouse model that they hope will improve understanding of all forms of the disorder and lead to the development of new treatments.

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The mouse model of dystonia (pictured) may help advance understanding of the condition, as well as other disorders that lead to secondary dystonia.
Image credit: U-M Health System.

To create their mouse model, the team looked to DYT1 dystonia. The researchers already knew that the DYT1 gene mutation causes brain cells to produce a less active version of a protein called torsinA (TOR1A), but the process that follows was a mystery.

Since DYT1 dystonia usually begins in early childhood, the researchers impaired the function of torsinA in the early brain development of mice using what they describe as “cutting-edge genetic technology.”

This caused the mice to simulate a human form of the disease, in which they did not develop dystonia until they reached preteen age in mouse years, and their symptoms stopped progressing after a period of time.

From analyzing the brains of these mice, the researchers discovered that a reduction of torsinA in the mice’s brains caused neurodegeneration – brain cell death – in some localized areas of the brain responsible for movement control. The researchers note that, just like movements in dystonia, neurodegeneration began in young mice and progressed for a period of time before becoming fixed.

Commenting on the team’s research, Dr. Dauer says:

We’ve created a model for understanding why certain parts of the brain are more vulnerable to problems from a certain genetic insult.

In this case, we’re showing that in dystonia, the lack of this particular protein during a critical window of time is causing cell death. Every disease is telling us something about biology – one just has to listen carefully.”

According to the U-M team, only a third of people with a DYT1 gene mutation develop dystonia, and those who have not developed the disease by their early 20s will never develop it. But why this is, the researchers do not yet know.

However, they suspect it may have something to do with a process that occurs in the early development of the brain, and they are already in the process of using their dystonia mouse model to find out.

But the potential of the mouse model does not end there. The team says it could help improve understanding of how dystonia occurs in people who have Huntington’s disease, Parkinson’s disease, or those who have movement problems as a result of stroke or a brain injury. This is known as secondary dystonia.

They note that in these cases, it is likely that the involuntary movements stem from an impairment in signaling from the brain to nerves that control movement. They say that with a “pure” dystonia mouse model, they can now investigate the mechanisms.

The U-M team says the mice will soon be available for other researchers to study.