Dystonia: Pathophysiology and Targeted Therapy

Abstract

DYT1 dystonia is a neurodevelopmental movement disorder caused by a mutation in the gene encoding the torsinA protein. The loss-of-function pathogenic mutation was identified ~25 years ago, but the underly pathophysiology of DYT1 dystonia remains poorly understood, hampering the development of more effective therapies. Our first set of studies explored a role for torsinB in DYT1 pathophysiology. TorsinB is a paralog of torsinA that was known to have conserved function with torsinA in a cellular phenotype. Whether this conservation would translate to neurological function was unknown, however. We demonstrated that torsinB is a potent modifier of DYT1 model phenotypes. Reducing levels of torsinB dramatically worsened DYT1 phenotypes. Conversely, torsinB overexpression prevented organismal, motor, and neuropathological phenotypes in torsinA deficient mice. These data provide proof-of-concept evidence for torsinB as a potential therapeutic target. A substantial body of preclinical work suggests that torsinA function is particularly critical during brain maturation. Consistent with these data, the symptoms of DYT1 dystonia emerge almost exclusively during a window from ~8-20 years of age. To rigorously test whether torsinA is uniquely required during a critical period and explore whether the efficacy of torsinA restoration is similarly age-dependent, we developed a novel mouse genetic tool that enables temporal and spatial control of torsinA expression. These studies demonstrated that torsinA is uniquely required during a critical period during neurodevelopment but appears to be entirely dispensable in adulthood. Similarly, torsinA repletion was highly effective in juvenile mice, but provided no benefit when applied in adult animals. These findings have important implications for the timing of torsinA (or torsinB) repletion as a therapeutic strategy in DYT1 patients. Extensive study of the cellular mechanism of these DYT1 models strongly implicated striatal cholinergic interneurons (ChIs) as central to dystonia pathophysiology. Notably, in all cases, we found that suppression of motor symptoms was correlated with prevention of ChI degeneration characteristic of these models. Additional existing data demonstrate that the emergence of abnormal movements in our DYT1 models occurs roughly coincident with ChI loss. To rigorously test necessity of ChI loss for abnormal movements, we generated a novel genetic reagent allowing us to selective rescue torsinA expression within these cells. We demonstrated that the selective prevention of ChI loss significantly suppressed abnormal twisting. We further demonstrate that abnormal function of the surviving ChIs emerges at the same time as abnormal twisting movements, and that reducing striatal cholinergic interneuron signaling through selective ablation or chemogenetic silencing suppressed motor dysfunction. These data establish the necessity of ChI loss for motor dysfunction, and demonstrate that suppressing the activity of these cells significantly reduced dystonia-like movements. In contrast to the early requirement for torsinA supplementation, these data identify a strategy to potentially suppress abnormal movements in DYT1 subjects with long established symptoms. Our findings therefore advance understanding of the circuit-level pathology of DYT1 dystonia and suggest novel therapeutic targets relevant to distinct phases of the disease.