Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements or postures. DYT1 early-onset generalized dystonia is the most common type among the genetic dystonias. Most of the individuals affected by DYT1 dystonia share a trinucleotide deletion (ΔGAG) located in exon 5 of DYT1 or TOR1A gene, leading to a loss of a glutamate amino acid residue for torsinA (torsinA∆E). The symptoms start from limbs and then become generalized. Affected individuals could be seriously disabled and need to use a wheelchair. Conditional knockout of torsinA in mice points to the involvement of multiple brain regions and cell types in the pathogenesis of DYT1 dystonia. These and other pathophysiological studies of DYT1 and other dystonias so far support a circuit or network model of dystonia pathogenesis. However, which brain region and neuronal types play a critical role in pathogenesis is unclear. Alterations of both the striatal dopaminergic and cholinergic systems appear to play a critical role in the pathophysiology of DYT1 dystonia. Dopaminergic modulation of striatal cholinergic interneurons (ChIs) is altered in multiple dystonia models that include DYT1 dystonia. Whether torsinA∆E in striatal ChIs has the cell-autonomous effect on striatal cholinergic dysfunction is not known. Preliminary studies of conditional knockin (KI) mouse models of DYT1 dystonia revealed dopaminergic and striatal medium spiny neurons (MSNs), but not ChIs, play a vital role in the pathogenesis of DYT1 dystonia. However, how torsinA∆E in MSNs and dopaminergic neurons lead to dystonia is unknown. These unknowns impede the progress in developing effective treatment for DYT1 patients, especially gene-based targeted therapy with CRISPR, antisense oligonucleotides, or small hairpin RNA. The broad, long-term objective of our research is 1) to determine the functional role of torsinA and the mechanism by which torsinA∆E leads to early-onset dystonia, 2) to develop novel and effective therapeutic treatment. The specific goal of this application is to generate and analyze five lines of conditional KI mice to understand the role of the striatal dopaminergic system and MSNs in the pathogenesis of DYT1 dystonia. We hypothesize that torsinA∆E in dopaminergic neurons and MSNs, but not ChIs, leads to abnormal firing of these neurons, decreased D1R and D2R in MSNs, altered striatal dopamine release, impaired corticostriatal LTD, altered direct and indirect pathways, and ultimately sustained muscle contractions and co-contractions that are characteristic of dystonia. Aim 1 will generate conditional MSN KI mice restricted to direct pathway, indirect pathway, or both and determine their phenotype. In Aim 2, we will introduce torsinA∆E specifically in dopaminergic neurons or ChIs and determine their dystonia-related phenotypes. The successful completion of the proposed research will significantly increase our understanding of the pathophysiology of DYT1 dystonia and aid the development of novel targeted treatments for dystonia patients.

Close to 500,000 Americans have dystonia, representing the third most common movement disorder after Parkinson’s disease and tremor. We will use molecular genetics, electrophysiology, and behavior analysis to determine protein function in specific cells and to gain a basic understanding of how cell-specific changes lead to dystonia-related motor deficits.