DMRF-Funded Researchers Discover First TorsinA Chaperone Protein

BiP Revealed as Potential Therapeutic Target

05/06/14

A study co-funded by the Dystonia Medical Research Foundation (DMRF) and published in the Journal of Biological Chemistry reveals a critical new clue about the origins of dystonia. Since 1997, scientists have known that a mutated protein called torsinA causes one of the most severe primary torsion dystonias, but the function of the protein remains unknown. A team of researchers have made important headway by uncovering a close relationship between torsinA and BiP, a well-studied cellular protein that was not known to have an association with dystonia until now.

Dystonia is a neurological movement disorder that causes involuntary, sustained muscle contractions resulting in twisting and repetitive movements and abnormal postures. The disorder affects men, women, and children of all ages and backgrounds, causing degrees of disability and pain from mild to severe. Dystonia is believed to result from improper signals in the nervous system that instruct muscles to contract involuntarily. Researchers do not yet fully understand the neurological mechanisms that cause the abnormal muscle contractions. Dystonia is the third most common movement disorder after essential tremor and Parkinson’s disease. The exact incidence and prevalence of dystonia are not known, but studies suggest no fewer than 300,000 people are affected in the United States and Canada.

Jeffrey Brodsky, PhD, Professor and Avinoff Chair of Biological Sciences at the University of Pittsburgh and Michal Zolkiewski, PhD, Associate Professor of Biochemistry and Molecular Biophysics at Kansas State University, co-led a study that used a sophisticated yeast cell model to investigate several proteins that interact with normal torsinA and its dystonia-causing mutant. The cell proteins belong to a family of chaperones, which are molecules that help other proteins take shape and function properly or, in case of faulty proteins, disassemble and deactivate them. When torsinA is mutated, it cannot function properly and becomes a target for chaperones—and particularly for BiP, which appears necessary to degrade mutant torsinA. BiP stabilizes both normal and mutated torsinA in mammalian cells; it is the first identified chaperone to act on torsinA. The function of BiP is well-understood, and development of potential treatments based on its interaction with torsinA may now be possible.

Brodsky explains, “For the first time we identified a cellular protein—known as BiP—that helps torsinA attain its proper shape in the cell. Because drugs that target cellular helpers such as BiP are in development, we hope that these might someday be used to treat primary torsion dystonia.”

The study also found that secondary mutations in torsinA, in addition to the specific mutation known to cause dystonia, amplify the effects of the defective protein when the dystonia-causing mutation is present.

Brodsky laboratory is known for its expertise in studying cellular proteins in yeast. The yeast genome makes it possible to conveniently track genes and proteins, especially those that have human equivalents, making it a valuable model for research on human diseases. Although the discovery that the BiP protein modulates torsinA function was made in yeast, the researchers were able to validate the results in human cells.

“The next step is to identify other cellular helpers that impact torsinA,” says Brodsky. This work is now conducted by DMRF research fellow Lucia Zacchi, PhD, Research Associate at Fundacion Instituto Leloir in Argentina, formerly a post-doctoral researcher in Brodsky lab. Brodsky adds: “Additional proteins from her continued analysis might one day also be targets of newly developed drugs to treat primary torsion dystonia.”

To learn more about the DMRF research efforts, visit www.dystonia-foundation.org/research

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