Research Funding in 2010

The DMRF awarded a record number of research grants and fellowships in 2010.

The caliber of the projects presented by this year's recipients is illustrative of how far the dystonia community has come. Because of our members' generous support, the DMRF is attracting today's brightest and most innovative investigators who are pushing the envelope, asking questions not asked before, and finding new answers. They are not only building our base of knowledge about what dystonia is and how it impacts the body, they are also thinking outside of the box at novel therapeutics that could potentially provide relief to many.

As a member of our Medical & Scientific Advisory Council noted, "The DMRF has funded more science this year than ever before. This is in spite of a bad economy and in a time when many
organizations are making cuts, not increases, in their programs. The DMRF should be commended for making science a priority."

CURE DYSTONIA INITIATIVE PROJECTS

Transgenic Rat Models for DYT1 Dystonia
Kathrin Grundmann, MD
University of Tubingen

The goal of this contract project is to develop the very first rat model of DYT1 dystonia. The first transgenic lines have been produced and are currently being tested using a variety of biochemical, molecular and behavioral techniques. The DYT1 transgenic rat will offer new opportunities to comprehensively study this form of dystonia.

Pathophysiological Role of the Cholinergic System in Animal Models of Dystonia
Angelika Richter, MD and Melanie Hamann, MD
Freie Universitat Berlin

The goal of this contract project is to investigate the role of the cholinergic system in a hamster model of dystonia. The neurotransmitter system is studied by treating the animals with a number of drugs and pharmacological agents affecting the cholinergic system by acting on specific receptors. These studies will deepen our understanding of the cholinergic system in dystonia as well as provide clues for drug design and development.

RESEARCH GRANTS

A Yeast Expression System To Uncover Fundamental Aspects of TorsinA Function
Jeffrey Brodsky, PhD
University of Pittsburgh

Even though much work has been devoted to understanding the function of the DYT1 gene and its corresponding protein, torsinA, the role played by this protein in the cell remains controversial. To rectify this deficiency in our knowledge, Dr. Brodsky and his collaborators will explore the differences between torsinA and the disease-causing mutant protein produced
in the common brewer's yeast, a well-developed model for studies on many human diseases. Ultimately, results from these studies may lead to the identification of new therapeutic targets.

Dopamine Neuron Development in a Novel Zebrafish Model of DYT1 Dystonia
Edward Burton, PhD
University of Pittsburgh

This work focuses on using a small fish (called a zebrafish) in order to understand human neurological diseases. Zebrafish share many similar genes with humans, including a version of the DYT1 gene. This model provides a simple experimental system in which it is possible to work out the mechanisms and gain insights into how the DYT1 gene affects the functions of dopamine in the developing brain. This work will generate a genetically modified zebrafish model that could be used in future studies to discover novel drug treatments for dystonia.

How Does the DYT1 Dystonia Mutation Alter TorsinA Function?
Rose Goodchild, PhD
University of Tennessee, Knoxville

The biological role of torsinA function is poorly understood and identifying this is a major aim for this research. Dr. Goodchild has identified that torsinA interacts with a previously undetected binding partner that is distinct to the previously characterized interactions. She also suggests that this binding partner plays a key role in normal torsinA function. The experiments
will further explore the relationship between these proteins and normal torsinA activity.

Activity-dependent Synaptic Plasticity in Globus Pallidus of Dystonia Patients
William Hutchison, PhD
Toronto Western Hospital

The basal ganglia receive input from higher levels of the brain (cortex) and direct their output to lower and higher motor centers (brainstem and thalamus). Long term changes in the responses of basal ganglia neurons to their inputs is referred to as synaptic plasticity, and this may be permanently altered in dystonia. Dr. Hutchison proposes to measure how the various groups of neurons in the output of the basal ganglia react to being electrically stimulated in different ways, and whether the different kinds of dystonias have different or the same characteristics. This novel work will give us a clearer understanding of the inhibitory mechanisms at work in subcortical structures of the brain so that specific drugs can be developed to target these specific mechanisms or prevent these alterations.

Whole Exome Sequencing in Dominantly Inherited Cervical Dystonia
Coro Paisan-Ruiz, PhD
University College London

Dr. Paisan-Ruiz intends to use whole exome sequencing technology to analyze three large families with typical cervical dystonia and identify the novel genes responsible for their disorder.
This revolutionary approach will enable her to perform a complete scan of all genes present in the human body and identify every genetic variant in these families. The expected outcome will be the identification of at least one (more likely three) novel genes for cervical dystonia.

To Investigate the Molecular Mechanism of DYT16 Dystonia
Rekha Patel, PhD
University of South Carolina

This proposal focuses on elucidating the molecular mechanism of two newly identified mutations in the PACT (DYT16) gene. The main hypothesis is that in DYT16 patients the mutant PACT proteins inhibit normal functioning of the stress-response pathway thus leading to the disease phenotypes. Dr. Patel will use molecular techniques to investigate if the described PACT mutations will cause a change in cellular response to stress signals. Such approaches should greatly enhance our understanding of the mechanisms that give rise to dystonia, and in the future allow us to translate basic scientific knowledge into novel therapeutic options.

Longterm-plasticity in Dystonia Patients Treated with Deep Brain Stimulation
John Rothwell, PhD
University College London

Globus pallidus internus (GPi) deep brain stimulation (DBS) has emerged as an effective treatment for some forms of dystonia. Dr. Rothwell has found physiological evidence that in primary dystonia neural reorganization or plasticity may play an important role in how DBS works. He hypothesizes that DBS acts to reduce abnormally high levels of plasticity in dystonia, and that this gives the rest of the motor system an opportunity to reorganize connectivity to more normal levels. If correct, this predicts that patients who show the largest effects on plasticity immediately after DBS will have the best clinical outcomes; conversely patients
in whom plasticity is not initially increased will respond less well to DBS.

Understanding the Role of the Cerebellum in Dystonia
Vikram Shakkottai, MD
University of Michigan

The cerebellum is involved in some forms of dystonia and cerebellar dysfunction typically causes loss of coordination or ataxia. How dysfunction of the cerebellum might contribute to both dystonia and ataxia remains a mystery. The current proposal takes advantage of mouse mutants that are defective in a gene that when mutated causes ataxia in humans. A similar mutation in rats also causes dystonia, and dystonia in this rat resolves completely following
removal of the cerebellum. Dr. Shakkottai will use electrophysiological techniques to look directly at the electrical properties of nerve cells in the cerebellum. The results are expected
to define a role for the cerebellum in human dystonia.

FELLOWSHIPS

The Role of the DYT6 Gene in Primary Dystonia
Tatiana Fuchs, PhD
Mount Sinai School of Medicine

Dr. Fuchs and others recently discovered the THAP1 gene as a cause of DYT6 dystonia in families of distinct ethnic origins. The THAP1 gene encodes a protein called a transcription factor that is thought to function by turning other genes on or off. In this project, she will perform a comprehensive mutation screen of this gene in both familial and sporadic patients with a
wide range of clinical symptoms from generalized to focal to determine the clinical characteristics associated with mutations in this gene. These studies should provide the basis for molecular diagnosis of DYT6 dystonia, identify genetic risk factors for focal dystonias, shed light on the underlying molecular mechanism and provide new directions for potential therapies.

Optogenetic Manipulation of Striatal Fast Spiking Interneurons in vivo
Daniel Leventhal, MD
University of Michigan

Abnormalities in almost every movement-related brain region have been found in various forms of dystonia. This research focuses on one cell type in one of these regions: the striatal fast spiking interneurons (FSIs), which appear to be important in the pathophysiology of some forms of dystonia. Within only the last few years the tools necessary to manipulate these cells independently of their neighbors in awake, freely behaving mice have been developed. Light sensitive proteins will be selectively inserted into these cells using genetic manipulations. By illuminating them with laser light, their firing will be suppressed. These experiments will
provide important data on the role of FSIs in normal and pathologic states, and may suggest new therapies for dystonias in which FSIs are causative.

A Novel Nonhuman Model to Probe Postural Control and Plasticity
Simon Overduin, PhD
University of California, Berkeley

Dr. Overduin will use data acquired from monkeys trained to perform a simple task, in which they use a joystick to reach towards targets following visual cues. He will correlate these recordings across levels in order to better understand what movement variables are actually being coded by the brain. The data will be complemented by electrical microstimulation recorded in the brain. This study has special relevance to dystonia because this disease may involve a malfunction of the brain's ability to program sequences of movements and postures. This research introduces a new reversible model of dystonia, one that may allow scientists to probe the brain's ability to plan movements in the normal state and to rehabilitate postural control in the diseased state.

Cerebellar Dysfunction in Focal Dystonia
Robert Raike, PhD
Emory University

Dr. Raike's previous studies in mice demonstrate that abnormal cerebellar activity is sufficient to produce generalized dystonia. Studies in patients and mice with dystonia demonstrate a clear association between dystonia and dysfunction within cerebellar Purkinje neurons. However, the role of Purkinje cell dysfunction in the severity and distribution of the dystonic movements has not been explored. Dr. Raike genetically eliminated the dysfunctional Purkinje cells from the mouse cerebellum and found that it is possible to alter the severity and distribution of dystonia. He will further study how the density and neuroanatomical pattern of Purkinje cell dysfunction contributes to the severity of dystonia. The research will provide insight into the neurological
basis of focal and generalized dystonias.

Investigation into the Cause of Myoclonus Dystonia
Amanda Smith, PhD
Ottawa Hospital Research Institute

Myoclonus dystonia (MD) is a neurological disorder characterized by rapid muscle contractions (myoclonus) and sustained twisting movements resulting in abnormal postures (dystonia). Forty percent of MD patients have mutations in the gene E-sarcoglycan (SGCE), which is a member of the sarcoglycan (SG) family. The aim of this project is to identify the components of
the SGCE complex in the brain using a method called tandem affinity purification-mass spectrometry. The goal is to identify the SG-complex in the brain including new members not seen in the complex found in muscle. By determining the proteins which interact
with SGCE it will be determined why the mutations in this gene cause MD.