Although the gene which causes DYT1 dystonia was discovered nearly a decade ago, the mechanism responsible for the symptoms in patients with this or many other forms of dystonia remains uncertain. This is a major obstacle to the rational design of effective therapies. During the prior period of support, we produced and characterized several mouse models of DYT1 in which there is expression of the abnormal torsinA protein throughout the brain, and found that these exhibit both behavioral as well as neurochemical abnormalities which appear to resemble aspects ofthe human disease. These have provided important insight into the effects of mutant torsinA on brain function. These models do not, however, resolve the question of how the abnormal protein leads to the phenotypic abnormalities, or identify the site of action. In this project, we will produce and study a novel series of mouse models with selective inactivation of torsinA, or knock-in ofthe DYT1 mutation. Using these, we will address the issue of whether selective inactivation in the cortex, striatum, or cerebellum is sufficient to produce behavioral and neurochemical abnormalities in the intact rodent. Given the strong evidence for involvement of the basal ganglia in many forms of dystonia, we will narrow the focus further by examining selective inactivation or knock-in ofthe DYT1 mutation in populations of striatal neurons, and within dopaminergic neurons. This project will also work closely with the other projects and cores, to identify opportunities to develop additional novel mouse models. Finally, we will seek to validate these models by assessing the effect of a drug treatment known to be effective in human dystonia, and establish a National Resource for distribution of these models to promote development of novel therapies. The overall goal of this work is to establish the anatomical site and mechanism of the dysfunction responsible for DYT1 and other dystonias, and enable targeted therapies for the disease.

Public Health Relevance

Dystonia is a common and disabling neurological disorder. Relatively little is known about the abnormalities in the brain which cause dystonia, and current treatments are not very effective. In this project we will use genetically engineered mice to study the brain circuits involved in dystonia, and establish new models which can be used to develop better treatments for dystonia.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
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Special Emphasis Panel (ZNS1-SRB-B)
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Massachusetts General Hospital
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