University of Texas Southwestern Medical Center, Kansas State University, and other institutions’ collaborative research may lead to the first universal treatment for dystonia, a neurological disorder that currently has no cure or effective treatment for all patients.
Affecting nearly half a million Americans, dystonia causes involuntary muscle contractions in many different parts of the body, resulting in slow repetitive movements, abnormal postures, or paralysis, the National Institute of Neurological Disorders and Stroke describes. Although some forms of dystonia are known to be genetic, the cause of the majority of cases is yet unknown.
Michal Zolkiewski, associate professor of biochemistry and molecular biophysics at Kansas State University, and Jeffrey Brodsky, from the University of Pittsburgh, co-led the study, in collaboration with Hui-Chuan Wu, a doctoral student in biochemistry and molecular biophysics at Kansas, researchers at the University of Texas Southwestern Medical Center and at the University of Adelaide, in Australia.
The study, called “The BiP molecular chaperone plays multiple roles during the biogenesis of TorsinA, a AAA+ ATPase associated with the neurological disease Early-Onset Torsion Dystonia”, was recently published by the Journal of Biological Chemistry and funded by the Dystonia Medical Research Foundation.
The study focused on a mutation in the TOR1A gene, which is associated with early-onset torsion dystonia (EOTD), the most severe type of this disorder, which typically affects adolescents before the age of 20. Across the U.S., approximately 1 in 30,000 people suffer from this type of dystonia, a study by the Orphanet Journal of Rare Diseases shows.
Currently, Zolkiewski says, there are some treatments for dystonia being tested, “but nothing is really available to those patients that would cure the symptoms completely.”
Researchers conducted the study based on the decade-old discovery that the mutation in the TOR1 A gene encodes the protein TorsinA, a protein present in everyone’s bodies that “appears to perform and important role in the nervous system,” Zolkiewski explains. However, he continues, nobody knows exactly what that role is, and there is thus no understanding of the link between the mutation and dystonia.
The team used yeast, one of the simplest living systems, engineering it to produce TorsinA, to study protein expression in a living organism. In result, they discovered that a second protein, named binding immunoglobulin protein (BiP) helps process the TorsinA, maintaing its active form. Researchers also found that this new protein guides TorsinA to being destroyed by cells if the protein is defective. Both proteins are carried by humans.
Basically, BiP helps other proteins to maintain their function. In fact, Zolkiewski says, it has a dual role, as it helps TorsinA and simultaneously leading to its degradation. Using the BiP protein in future study, the team hopes to be able to treat dystonia with this protein, as modulating BiP in human cells would affect TorsinA.
However, Zolkiewski warns, since it is still unknown what function TorsinA has, it may not be possible to design a treatment based on that protein. “We know what BiP does, however. It is a pretty well-studied chaperone, which makes it much easier to work with,” he concluded.