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Scientists track protein linked to neurological movement disorder

St. Louis, May 17, 2004 — A team led by researchers at Washington University School of Medicine in St. Louis is one step closer to understanding the function of a protein linked to an inherited form of the movement disorder dystonia.

The protein, torsinA, is defective in patients with DYT1 dystonia, an inherited condition that causes uncontrollable movements in the limbs and torso. Learning what torsinA does could be an important step toward developing a treatment for the disorder.

“The hope is that understanding as many forms of dystonia as we can will give us some insight into how we might treat movement disorders generally,” says Phyllis I. Hanson, M.D., Ph.D., assistant professor of cell biology and physiology and senior investigator for the study. “Any new insights might also be helpful for understanding secondary dystonias. These are conditions in which dystonia is a complication of another disorder, such as Parkinson's disease.”

The study is available in the early online edition of the Proceedings of the National Academy of Sciences and will appear in the May 18 print edition of the journal.

According to the Dystonia Research Foundation, approximately 300,000 Americans have some form of primary dystonia. Dystonia is a neurological movement disorder characterized by involuntary muscle contractions that force certain parts of the body into abnormal, sometimes painful, movements or postures. Dystonia can affect any part of the body including the arms and legs, trunk, neck, eyelids, face or vocal cords. DYT1 dystonia affects about 10,000 Americans.

Co-author Xandra Breakefield, Ph.D., professor of neurology at Harvard University, led the team that identified the gene for DYT1 dystonia in 1997. Researchers later found the gene makes torsinA. Study of torsinA's structure suggested it belongs to a family of proteins known as AAA+ ATPase proteins. This protein family typically helps cells recycle resources by breaking down assemblies of other proteins and molecules into their components, like disassembling a car for reuse of its parts.

Hanson, who studies behavior of cell membranes, previously found torsinA in the endoplasmic reticulum, a large compartment that has branches that pass through various regions of the cell.

For the new study, she engineered defective copies of the torsinA gene and inserted them into cultured mammalian cells. Hanson designed one of the defective genes to make a form of torsinA that would stick permanently to adenosine triphosphate (ATP), a compound cells use to move energy around. Breaking down ATP normally provides torsinA with a great deal of energy, probably enabling it to perform its main job. Hanson hoped making torsinA stick to ATP would trap it at its normal site of action, revealing where in the cell the protein usually works.

The TorsinA that was stuck to ATP moved into the nuclear envelope, the portion of the endoplasmic reticulum that surrounds the nucleus, the central compartment of the cell where DNA is kept.

“Based on what's known about other proteins like torsinA, we figure this means torsinA is probably taking something apart in the nuclear envelope,” Hanson says. “The questions are: What is it taking apart and how is that important for the normal structure and function of the nuclear envelope? And how is that activity perturbed by the genetic mutation responsible for DYT1 dystonia?”

Defects in other proteins found in the nuclear envelope recently have been linked to several diseases, including a form of muscular dystrophy and a neuropathy.

“Like any other research, this finding has its caveats,” Hanson says. “But we think that there's likely to be some important function that torsinA performs in the nuclear envelope.”

Hanson plans further studies to determine torsinA's function.

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Naismith TV, Heuser JE, Breakefield XO, Hanson PI. TorsinA in the nuclear envelope. Proceedings of the National Academy of Science, May 18, 2004.

Funding from the National Institutes of Health, the Dystonia Medical Research Foundation, the W.M. Keck Foundation, the McKnight Foundation and the Jack Fasciana Fund for Support of Dystonia Research.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked second in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.