Dystonia is a debilitating clinical condition in which the normal control of movement is subverted by an overflow of muscle activation. This results in twisting movements and postures, and a major impact on quality of life. Recent work points to roles for the basal ganglia, thalami, cortex and cerebellum in dystonia, but there are different theories about the underlying mechanisms and pathways. Traditionally dystonia has been thought to be a disorder of circuits, meaning aberrant integration of neuronal firing. Nonetheless, many types of dystonia are permanent, and recent human brain imaging and post-mortem pathology studies indicate that there can be structural changes. For future progress a mouse model is needed that would be amenable to pharmacological, surgical, physiological (DBS), and genetic tests and interventions. Viable adult mice carrying human dystonia genes have so far failed to manifest dystonic symptoms. This leaves mutant animals that have additional pathologies, or that were injected with toxins, as the only evidence until now that rodents have circuitry to exhibit the disorder. A new spontaneous mutant mouse line exhibits movements and postures typical of a segmental dystonia affecting hindlimbs and tail, with co-contraction of opposing muscles. The mouse has the unusual properties for a neurological mutation of showing dominant inheritance with high penetrance;adult-onset;a lack of incapacitating deficits;lifespan of at least 18 months so far;and easy breeding. Although the symptoms are severe, a key feature is that the mice are capable of normal walking and running on a wheel, functions that are largely mediated by spinal pattern generators and spinal sensorimotor integration. This strongly suggests that the impairment is supra-spinal. Genetic mapping found two loci including a modifier gene, and ruled out known neurological mutations. The core objectives are to experimentally identify the affected genes, establish tests for quantifiable trais, and test initial hypotheses for underlying pathology and mechanisms.
Specific Aim 1 is to do whole exome sequencing to identify the genes. Candidate variants will then be validated and tested.
Specific Aim 2, which will be carried out in parallel, will be to determine quantifiable motor deficits and electrophysiological fundamentals as a basis for work on a cure.
Specific Aim 3, also to be done in parallel, will be to look carefully for evidence of either pathology or of pathway activation in brain, spinal cord, peripheral nerve, and muscle. This plan of basic characterization is essential to test the hypothesis that the mouse merits wide-spread use as a model of dystonia. The project is high-risk because of uncertainty about what genetic and neurological features will be discovered, and high-reward because the mouse's consistency of symptoms, ease of propagation, and lack of special husbandry requirements will make it a very practical tool.

Public Health Relevance

A mouse model of dystonia is needed to investigate genetic, physiological, pharmacological, and surgical approaches to treatment, but so far an animal model with typical, pure symptoms of dystonia has not been reported. Here we will characterize a new spontaneous mutant mouse with very favorable features. The proposal is to determine its genetics and evaluate it as model of the disorder suitable for wide-spread use.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Cell Death and Injury in Neurodegeneration Study Section (CDIN)
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Sieber, Beth-Anne
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Massachusetts General Hospital
United States
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