“This work is a natural extension of our earlier studies, supported by DMRF, which showed that the DYT1 mutation impairs torsinA function,” explains Dauer. “What is new about this study—and very exciting to us—is linking impaired torsinA function to the onset of abnormal dystonic movements.”
DMRF President Art Kessler, who was diagnosed with DYT1 dystonia as a child, remarked, “This is a critical milestone in dystonia research. Congratulations to everyone who helped make it happen.”
Dauer and colleagues have been working for years to figure out how and why a mutation in the DYT1 gene results in childhood onset dystonia. In this study, published in the Journal of Clinical Investigation, Dauer focused on developmental aspects of DYT1 dystonia, which typically starts in children between the ages of 8 and 11, seemingly out of nowhere, following a normal early childhood. However, even if a child has the DYT1 gene mutation known to cause this form of dystonia, if he/she reaches adulthood without symptoms, the likelihood of ever developing dystonia is reduced to next to nothing. This suggests specific changes in the early stage of brain development make the nervous system vulnerable to the effects of the genetic mutation. Once that window of time has passed, for unknown reasons, the risk of dystonia essentially disappears.
Dauer and his team have developed a genetic mouse model of DYT1 dystonia that mimics the human disorder. These genetically engineered mice demonstrate overt movement symptoms of dystonia, marked by patterned twisting and fixed postures in the limbs. The symptoms appear in young mice at a stage of brain development equivalent to the typical human age of onset. These mice provide a unique and direct opportunity to study the effects of abnormal torsinA in the brain.
The mouse model reveals a correlation between abnormal torsinA and neurodegerenation, the death of brain cells. Recent imaging studies have also observed subtle cell loss in specific brain structures in select dystonias. However, unlike in Parkinson’s disease or Alzheimer’s disease, in which neurodegeneration progresses aggressively over widespread areas of the brain, the neurodegeneration seen in the DYT1 mouse model occurs only in specific brain structures involved in movement control and only for a specific period of time that coincides with the onset of dystonia symptoms.
Dauer explains: “We’ve created a model for understanding why certain parts of the brain are more vulnerable to problems from the DYT1 gene mutation responsible for dystonia. In this case, we’re showing that in dystonia, the lack of this particular protein during a critical window of time is causing cell death.”
The research indicates that the loss of even a small number of brain cells from specific structures in the brain could disrupt the development of circuits critically involved in movement. Previous studies have shown that torsinA is engaged in the quality control of other proteins in the cell, so surviving brain cells may be impaired due to torsinA inability to function properly when mutated.
The study makes a critical, experimentally testable connection between impaired torsinA function, neural circuits, and dystonia symptoms—a tour de force of experimental neuroscience that opens up countless opportunities for future studies. The mouse model will be available to other researchers to help accelerate understanding of all forms of dystonia and the search for treatments.
Work in the Dauer lab continues as well: “We are pursuing several lines of work stemming directly from these studies. One question we are pursuing is why some, but not other, neurons are injured by deficient torsinA function. We think this is a crucial piece of the puzzle to unravel, because if we understand why some neurons are able to withstand the effects of the DYT1 mutation, we may be able to mimic that difference to protect the vulnerable cells. Another direction we are pursuing is using these mice to test potential therapeutics and—with colleagues here at U-M including DMRF-funded investigator Dr. Dan Leventhal—to better understand the changes in brain circuitry that are causing the abnormal movements.”
In 2006, Dauer was the very first recipient of the Stanley Fahn Award, the DMRF’s most prestigious research grant. He is a past member of the Medical & Scientific Advisory Council. Co-author Lauren Tanabe, PhD, was awarded a two-year DMRF research fellowship in 2011.
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.
The mission of the Dystonia Medical Research Foundation (DMRF) is to advance research for improved dystonia treatments and a cure, promote awareness and education, and provide support resources to affected individuals and families. The DMRF was founded in 1976 and continues to be the world’s leading dystonia patient organization. The DMRF can be reached at 800-377-DYST (3978) or www.dystonia-
Citation: TorsinA Hypofunction Causes Abnormal Twisting Movements and Sensorimotor Circuit Neurodegeneration. Liang CC, Tanabe LM, Jou S, Chi F, Dauer WT. J Clin Invest. 2014 Jun 17. pii: 72830. doi: 10.1172/JCI72830. [Epub ahead of print]