Healthcare (Commonwealth Union) – A protein known as torsinA is vital in the initial growth of neurons, deciding where nuclear pores should be positioned in the membrane surrounding the nucleus of nerve cells, according to a study conducted by researchers at UT Southwestern Medical Center. This research, appearing in Nature Cell Biology, addresses longstanding questions about torsinA’s purpose and may pave the way for treatments for a rare movement disorder called DYT1 dystonia, which is caused by a torsinA mutation.
“The function of torsinA has been elusive. This work demonstrates that torsinA is involved in the spatial organization of nuclear pore complexes and suggests dysregulation of this process during neurodevelopment could contribute to long-lasting neuronal deficits,” explained Samuel Pappas, Ph.D., Assistant Professor in the Peter O’Donnell Jr. Brain Institute and of Neurology at UT Southwestern.
Dr. Pappas collaborated on the study with Dr. William Dauer, Director of the O’Donnell Brain Institute and Professor of Neurology and Neuroscience, and Dr. Sami Barmada, Associate Professor of Neurology at the University of Michigan. The study’s lead author is Dr. Sumin Kim, who completed her Ph.D. at the University of Michigan, where she was co-supervised by Drs. Pappas, Dauer, and Barmada.
DYT1 dystonia is characterized by involuntary twisting and tremors in the arms and legs, typically beginning in childhood. Epidemiological research estimates that this inherited disorder affects between 54,000 and 80,000 people in the U.S. However, nearly three times as many individuals carry the torsinA gene mutation responsible for DYT1 dystonia. It remains unclear why symptoms emerge in childhood, how the torsinA mutation leads to the condition, and why many carriers do not develop symptoms. Understanding the role of torsinA is key to addressing these unanswered questions, according to Dr. Pappas.
In previous studies, Dr. Pappas and his team discovered that when the gene responsible for torsinA is deleted early in development in animal models—but not in adulthood—neurons form nuclear pore complexes (NPCs) in clusters rather than evenly across the nuclear membrane. These small openings in the nuclear envelope are essential for the exchange of proteins and genetic material between the cell nucleus and the cytoplasm, the fluid within cells.
To explore how torsinA might influence NPC distribution, Drs. Pappas, Dauer, Barmada, and their team monitored the number and positioning of these structures in neurons cultured from animals shortly after birth. In the first few days, these neurons produced a higher number of NPCs, which aligned with the maturation of neuronal circuits. Further experiments in cultured neurons revealed that deleting torsinA did not affect the total number of NPCs but altered their location on the nuclear envelope, leading to the clustering observed in the prior study.
To study torsinA’s role in live animals, the researchers engineered a mouse model where a protein within the NPC was labeled with a fluorescent tag. This allowed them to observe that the clusters consisted of newly formed NPCs unevenly distributed across the nuclear membrane. Additional experiments showed that neurons lacking torsinA, or with the mutated form of the gene found in DYT1 dystonia patients, developed abnormal swollen regions on the nuclear envelope before NPCs appeared during maturation. These “blebs” were located where the NPC clusters formed. Using super-resolution microscopy, the team confirmed that while the NPCs themselves appeared structurally normal, their distribution within the nuclear envelope was abnormally clumped.
Dr. Pappas clarified that these findings collectively imply torsinA determines the placement of NPCs during a crucial phase early in neuron development, a process essential for normal neuronal function later in life and corresponds with the onset of DYT1 dystonia symptoms. Additional research could help scientists uncover the distinction between individuals who possess the disease-causing mutation and develop symptoms, and those who do not. Ultimately, these discoveries may lead to treatments for the disorder.
