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Of mice and muscles: Dystonia discovery may help patients

Persistent team of U-M scientists study neurological condition that twists muscles of kids and adults

Dystonia causes muscles in the neck and limbs to twist or contract uncontrollably, in children and adults.

Dystonia causes muscles in the neck and limbs to twist or contract uncontrollably, in children and adults.

Twist and hold your neck to the left. Now down, and over to the right, until it hurts.

Now imagine your neck – or arms or legs – randomly doing that on their own, without you controlling it.

That’s a taste of what children and adults with a neurological condition called dystonia live with every day – uncontrollable twisting and stiffening of neck and limb muscles.

The mystery of why this happens, and what can prevent or treat it, has long puzzled doctors, who have struggled to help their suffering dystonia patients.

But a persistent team of University of Michigan scientists have finally opened the door to a new way of answering those questions and developing new options for patients.

They’ve bred new strains of mice that closely mimic a human form of the disease, and made important early discoveries in those mice’s brains.

They’ll soon make the mice available for researchers everywhere to study, to accelerate understanding of all forms of dystonia and the search for better treatments. The lack of such mice has held back research on dystonia for years.

Persistence pays off

The U-M team’s success in creating a mouse model for the disease came only after years of stubborn, persistent effort – often in the face of setbacks and failure.

Led by U-M neurologist William Dauer, M.D., the team tried to figure out how and why a gene defect leads to an inherited form of dystonia that, intriguingly, doesn’t start until the pre-teen or teen years, after which it progresses for many years but then stops getting worse after the person reaches their mid-20s.

Using the childhood onset as a clue, Dauer and his team used cutting-edge genetic technology to breed mice that closely mimic the human disease.

Just like kids with a genetic form of dystonia, the mice don’t develop dystonia until they reach preteen age in “mouse years,” and their symptoms stop getting worse after a while.

The researchers saw clear signs of accelerated brain cell death in muscle-controlling areas of the brains of mice with dystonia (right column) compared with others.

The researchers saw clear signs of accelerated brain cell death in muscle-controlling areas of the brains of mice with dystonia (right column) compared with others.

With this powerful tool in hand, Dauer’s team were now able to peer into the brains of these animals to begin to unravel the mysteries of the disease.

They’ve seen signs of a process called neurodegeneration – death of brain cells called neurons – in areas of the brain that control muscle movements. And it happened only during a window of time, then stopped – just like in people.

More discoveries to come

Dauer and his team don’t yet know why only one-third of humans who carry the gene mutation develop this form dystonia during their school years — and why those who don’t develop the disease before their early 20s will never go on to develop it.

They believe some critical events during the brain’s development in infancy and childhood may have to do with it – and they’re already working to explore that question in mice.

They also believe their mouse model will help them and other researchers understand how dystonia occurs in people who have Parkinson’s disease, Huntington’s disease, or damage caused by a stroke or brain injury. Some people develop dystonia without either a known gene defect or any of these other diagnoses – a condition called idiopathic dystonia.

In all these cases, dystonia’s twisting and curling motions likely arise from problems in the area of the brain that controls the body’s motor control system.

In other words, something’s going wrong in the process of sending signals to the nerves that control muscles involved in movement. Studying a “pure” form of dystonia using the mice will allow researchers to understand just what’s going on.

The team’s ultimate goal is to find new treatments for all kinds of dystonia. Currently, children, teens and young adults who develop it can take medications or even opt for a form of neurosurgery called deep brain stimulation. But the drugs carry major side effects and are only partially effective – and brain surgery carries its own risks. Dauer and his team are working to screen drug candidates.

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new_logos_180x1806For more than 160 years, the University of Michigan Health System has been a national leader in advanced patient care, innovative research to improve human health and comprehensive education of physicians and medical scientists. The three U-M hospitals have been recognized numerous times for excellence in patient care, including a #1 ranking in Michigan and national rankings in many specialty areas by U.S. News & World Report.