Dystonia is a movement disorder characterized by muscle contractions that cause debilitating twisting movements and postures. DYT1 dystonia, the most common inherited dystonia, is a severe form of generalized dystonia. DYT1 dystonia is caused by a mutation in the TOR1A gene, resulting in a glutamic acid deletion in the TorsinA protein. Despite the identification of a causal mutation, our understanding of the mechanisms that lead to abnormal movements is incomplete. This limited understanding of pathological mechanisms likely explains, in part, why there are few therapeutics available to treat the disorder. The preferred oral therapeutic for dystonia is the non-selective muscarinic antagonist trihexyphenidyl (THP). While THP is an effective treatment for many patients, its utility is limited by dose-limiting side effects. To date, the mechanism of action of THP in DYT1 dystonia is unknown. One clue to THP?s therapeutic mechanism is the fact that dopamine (DA) dysfunction in the basal ganglia has been consistently implicated in many forms of dystonia. Humans with DYT1 have normal striatal tissue DA but have abnormal DA metabolite ratios. Mice harboring the human DYT1-causing mutation also have normal striatal tissue DA, but reduced extracellular DA in the striatum. This evidence suggests that striatal DA release is reduced in DYT1 mice and humans. Importantly, preliminary data collected in our lab shows that THP effectively enhances striatal extracellular DA concentrations. However, the exact muscarinic receptor subtypes responsible for this effect are unknown. This is a critical piece of information for developing new treatments for dystonia, without the adverse side effect profile of THP. The purpose of this proposal is to determine the muscarinic receptor subtype(s) responsible for the DA-enhancing effect of THP and the improvement of motor symptoms in DYT1 dystonia.
Dystonia is a movement disorder characterized by debilitating muscle contractions and abnormal movements. The preferred medication for dystonia treatment is the non-selective muscarinic antagonist trihexyphenidyl, which, while effective in many patients, has limited therapeutic potential due to dose-limiting side-effects likely caused by its non-selectivity. This proposal aims to dissect the mechanism of action of trihexyphenidyl in order to develop new, selective treatments for dystonia, which will avoid the dose-limiting side effects that hamper current treatment.