Pathomechanisms of Dopamine Dysregulation in DYT1 Dystonia: Targets for Therapeutics
Abstract
Dystonia, the third most common movement disorder after tremor and Parkinson s disease, is characterized by involuntary muscle contractions that cause debilitating twisting movements and postures. The causes of dystonia are not clearly understood, but abnormal signaling by the neurotransmitter dopamine occurs in many inherited forms of dystonia. Dystonia can also occur in Parkinson s disease, where there is frank loss of dopamine neurons. Abnormal dopamine signaling is also seen in early onset torsion dystonia (DYT1 dystonia). This is important because DYT1 dystonia is used a prototype for understanding dystonia whereby discoveries made regarding DYT1 dystonia often generalize to other dystonias. Although DYT1 dystonia is linked with abnormal dopamine signaling, the nature of the dysfunction is not clear. Because DYT1 dystonia is relatively rare, studies examining dopamine signaling are not easily accomplished in human subjects. Instead, we will use mice that carry the mutation associated with DYT1 dystonia and can be used to explore pathomechanisms. In fact, abnormalities in dopamine signaling that are observed in patients with DYT1 are also observed in these mice. Findings in both mice and humans point to a reduction in dopamine release as the most likely explanation for the abnormal dopamine neurotransmission, but the underlying problems that cause the abnormal release are unknown. The goal of this study is to understand the biological problems underlying the abnormal dopamine neurotransmission and the mechanism of action of trihexyphenidyl, the drug most commonly used to treat dystonia. To accomplish these goals, we will identify the causes of the abnormal dopamine signaling by examining how dopamine is packaged within neurons, how it is prepared for neurotransmitter release and how dopamine release is controlled. This is important because understanding the biochemical problems is necessary to design new therapeutics that precisely target the problem. Finally, we will examine the effects of the muscarinic receptor antagonist trihexyphenidyl (Artane) to determine how they alter the defective dopamine signaling. This is important because insight into how these drugs affect dopamine signaling will provide the information necessary for improving drug therapies. The findings of this proposal will have a direct impact on our understanding of the biologic defects underlying dystonia and the development of therapeutics. In terms of short-term impact, many drug companies are currently developing novel and selective muscarinic receptor antagonists to increase efficacy and reduce side effects. However, it is not yet clear which muscarinic receptor is an appropriate target for dystonia. Our studies will provide information to guide target selection and will have an immediate effect on compounds that move to clinical trial as these results will provide information on both beneficial targets and deleterious targets, information that is currently lacking. In terms of long-term impact, understanding the dopaminergic defects in DYT1 dystonia will elucidate novel targets for therapeutics that will be relevant to many forms of dystonia, not just DYT1 dystonia, because abnormalities in dopaminergic transmission are observed in many different forms of dystonia.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510545
Entities
People
- Ellen Hess
Organizations
- Emory University
- United States Army