TorsinA Restoration in DYT1 Dystonia Model Identifies a Critical Therapeutic Window

Dr. William Dauer is a past DMRF grant recipient and member of the Medical & Scientific Advisory Council.

A protein in the brain called TorsinA is known to cause childhood onset dystonia when it cannot function properly due to genetic changes in the DYT1/TOR1A gene. This makes TorsinA a possible target for new treatment approaches. Numerous research teams across the world are investigating whether restoring normal TorsinA function could be an effective strategy to reverse or even prevent dystonia.

One of the most notable aspects of DYT1/TOR1A dystonia is that symptoms typically begin during a very specific age window, approximately 9-12 years of age. Even if a person has the DYT1/TOR1A gene variant, if they reach age 30 without developing symptoms, they almost never develop dystonia. This suggests there is something about the young developing brain that makes it vulnerable to dysfunctional TorsinA.

William Dauer, MD, Director of the Peter O’Donnell Jr. Brain Institute and Professor of Neurology and Neuroscience at UT Southwestern Medical Center, led a study to specifically test whether TorsinA function is uniquely necessary during a critical neurodevelopmental period, and whether genetic rescue is similarly only possible during a specific period of brain development. To rigorously address these questions, he and his team developed a series of experiments in mice. They found that embryonic suppression of TorsinA caused dystonia-like motor symptoms and observable changes in the brain. By contrast, TorsinA suppression in adult mice caused no apparent abnormalities. Furthermore, the ability to correct the TorsinA dysfunction and reduce dystonia symptoms was only possible during specific periods of brain development. Restoring TorsinA expression in young symptomatic mice reversed the abnormal movements and changes in the brain. By contrast, restoring TorsinA expression in adult mice had no effect. These important findings demonstrate that normal TorsinA function is critical to early brain development and suggest that TorsinA-based therapeutics may need to be targeted early in the course of DYT1/TOR1A dystonia.

Li J, Levin DS, Kim AJ, Pappas SS, Dauer WT. TorsinA restoration in a mouse model identifies a critical therapeutic window for DYT1 dystonia. J Clin Invest. 2021 Mar 15;131(6):e139606.

The Dystonia Medical Research Foundation is a 501(c)(3) non-profit organization dedicated to advancing research for improved dystonia treatments and ultimately a cure, promoting awareness, and supporting the well-being of affected individuals and families.