Primary dystonia is a neurological disorder characterized by disabling, abnormal, involuntary movements, which can have devastating consequences for the patient. Interestingly, primary dystonia exhibits features of both neurological and psychiatric disease. Like psychiatric disease, the condition is characterized by abnormal functioning of a structurally normal-appearing brain, and can disrupt processes of normal development or neuronal plasticity. Like other neurological diseases, primary dystonia is a motor system disorder that can be caused by several different single gene mutations. These features suggest that an improved understanding of this illness could provide valuable insights into clinically important aspects of nervous system function.
The most common genetic form of primary dystonia is DYT1 dystonia, a dominantly inherited disease caused by a deletion in TOR1A that removes a single glutamic acid (ΔE) from the protein torsinA. TorsinA is AAA+ protein that resides within the endoplasmic reticulum/nuclear envelope endomembrane system. We have discovered that neurons have a unique requirement for nuclear envelope-localized torsinA function, and have begun to dissect the mechanisms underlying this neural specificity. These studies involve characterization of a stem cell-based model of torsinA function that mimics the neuronal selective alterations seen in torsinA mutant mice. We have also begun using PET and DTI brain imaging to identify the dysfunctional neural circuit in DYT1 disease mutant "knock in" mice, and we are currently working to dissect the cellular and molecular correlates of these imaging findings.