Current Research Investigations

The ultimate goal of the Science Program is to support the discovery of improved therapies and a cure.

To achieve this goal, the DMRF is dedicated to stimulating the field of dystonia research and supporting the collaborations and projects necessary to accelerate progress.

The DMRF is also devoted to attracting young, talented investigators who are becoming the next generation of leaders in dystonia research. In many cases, DMRF grant and fellowship awards are intended to help investigators gather enough preliminary data to make them eligible for much larger grants from agencies such as the National Institutes of Health.

The DMRF is proud to announce this year's truly exciting research projects. Each of these projects is meaningful because it addresses one or more of the core directions necessary to advance the field. These core directions include furthering our fundamental understanding of what dystonia is, uncovering the mechanisms in the nervous system that leads to symptoms, creating models of dystonia to use in experiments, and discovering targets for new and improved therapeutics designed specifically to treat dystonia. Several of this year's projects are testing brand new hypotheses into the causes of dystonia.

Congratulations to this year’s award recipients, and infinite thanks to our supporters for making this research funding possible.

Research Grants & Contracts

Research grants are available in support of hypothesis-driven research at the genetic, molecular, cellular, systems, or behavioral levels that may lead to a better understanding of the pathophysiology or to new therapies for any or all forms of dystonia. Contracts provide the opportunity to direct research through the identification of specific, milestone-driven projects to be conducted by identified investigators and closely monitored by the DMRF’s Chief Scientific Officer.

Neuroanatomical Substrates for Disrupted Eif2alpha Signaling in Dystonia
Nicole Calakos, MD, PhD, Duke University (USA)

Although dystonia is among the top three most common conditions evaluated in neurological movement disorder clinics, the precise mechanisms for dystonia are poorly understood and there are no known disease-modifying treatments. This project proposes to advance our understanding of dystonia mechanisms and to explore specific cellular pathways to target in order to treat the disease. Observations in multiple forms of dystonia have implicated a specific cellular pathway in the brain as a central source of dysfunction. This pathway is involved in responding to cellular stressors and mediating plasticity responses in the brain. This study proposes to identify the brain regions, cell types, and developmental periods in which the pathway’s activation is disrupted in dystonia mouse models and to test whether a genetic manipulation that would boost the pathway’s activity will reduce negative effects of the DYT1 mutation. This knowledge will advance our understanding of the cellular mechanism of dystonia and provide key proof-of-principle experiments to determine whether targeting the pathway is beneficial.

Tremor, Ocillations, Synaptic Plasticity, and DBS for Dystonia
William Hutchison, PhD, Toronto Western Hospital (Canada)

intervention by chronic deep brain stimulation (DBS) in the globus pallidus internus (GPi) has been found beneficial in treating severe cases of dystonia but the mechanisms underlying the pathophysiology and the DBS treatment are poorly understood. This study seeks to better understand how and why DBS works. The researchers propose using microelectrode recordings of dystonia patients to investigate cell activity in an area of the brain called the the globus pallidus. In addition, they will use microstimulation and focally evoked field potentials (fEPs) to determine whether there are functional abnormalities in inhibitory processes at neurosurgical target sites. They will obtain synaptic plasticity measures and correlate these to the type and severity of dystonia using clinical rating scores. The goal is to gain insight into the mechanisms of tremor and dystonia. The researchers hope to possibly translate this knowledge to develop new targets for pharmacological intervention. This project is funded by Dystonia Medical Research Foundation Canada.

Determining the Role of Torsin in Nuclear Pore Complex Assembly
Patrick Lusk, PhD, Yale University (USA)

DYT1 dystonia is caused by an underlying genetic abnormality that leads to the expression of a defective form of a protein called TorsinA in cells throughout the body. Although TorsinA’s substrates or its function have not yet been identified, several lines of data support that it works to maintain the integrity of the nuclear membranes that enclose and protect the human genome. For example, the morphology of the nuclear membranes is disrupted in neurons expressing mutant TorsinA with distinct herniations. This research group has recently established that these herniations result from a disruption in the assembly of nuclear pores, the nuclear membrane’s essential transport channels. They uncovered a novel link between nuclear pores and TorsinA. Researchers hypothesize that a disruption of nuclear pore assembly by mutant TorsinA leads to the loss of the highly regulated and essential transport of specific cargo molecules in and out of the cell nucleus. They will use experimental strategies that draw on the collective expertise of a consortium, which includes experts in nuclear transport and the biochemistry and cell biology of Torsins, to test this hypothesis. Data from the proposed study are expected to substantially advance our understanding of Torsin (dys)function, and to facilitate the development of more effective treatment strategies.

Synaptic Plasticity in a Mouse Model of Paroxysmal Dystonia
Alexandra Nelson, MD, PhD, University of California San Francisco (USA)

The underlying causes of dystonia are not known, though the fact that the brain appears normal in many forms of dystonia suggests that the connections between brain regions, or the activity within these brain regions, are responsible. This study uses a new mouse model of dystonia, based on a genetic form of the human disease called paroxysmal kinesigenic dystonia (PKD), to dissect how the connection between cells is altered, putting patients at risk of developing dystonia. This project will first test the movement of PKD model mice versus their healthy siblings, looking for evidence of dystonia. The second phase of the project will involve making recordings of the connections between cells in two brain regions believed to contribute to dystonia: the striatum and the cerebellum. Researchers hope this study will form the foundation for a larger research program aimed at understanding the fundamental cellular and circuit changes that cause dystonia, so that new and more effective drugs or brain stimulation approaches can be developed.

Investigation of Striato-Pallidal Connections in a Mouse Model of DYT1 Dystonia
Giuseppe Sciamanna, PhD, University of Rome tor Vergata (Italy)

DYT1 dystonia pathophysiology is not well understood, but evidence points to alterations of the basal ganglia circuit. Moreover, it has been suggested that external globus pallidus (GPe) may be strongly involved in generation of dystonic symptoms. Alterations in the firing pattern of GPe neurons in both humans and rodent models have been found. GPe receives strong inhibitory input from the striatum and it projects to all other nuclei of basal ganglia. Thanks to this large interconnection, GPe has a crucial role in processing of sensorimotor information and its abnormal activity can have major consequences for basal ganglia function and activity. To date no exhaustive investigation has been conducted about the role of GPe in dystonia. By means of electrophysiological, optogenetic, and biochemical approaches, this project aims to investigate in a mouse model of DYT1 dystonia, potential abnormality in neural activity of GPe neurons together with alterations of mutual synaptic connection between striatum and GPe. The project will characterize for the first time the role of GPe in the pathogenesis of dystonia investigating how the interaction among distinct basal ganglia nuclei may be altered, and could represent a crucial step to understand the cellular basis of dystonic symptoms.

Dystonia-associated Endoplasmic Reticulum Defects and the (De)regulation of Neurotransmission
Patrik Verstreken, PhD, VIB Leuven (Belgium)

TorsinA is the protein encoded by the DYT1 dystonia TorsinA gene. This research group recently identified that mouse TorsinA, human TorsinA, and fly Torsin regulate cellular lipid metabolism. Lipids are small molecules that are the building blocks of cell membranes. There are a wide variety of different types of lipids, and their data indicates that Torsin activity is critical for the normal balance of lipid production. The hypothesis is that abnormal lipid biology is the origin of DYT1 dystonia. The fruit fly is an ideal system to study individual neurons, rapidly introduce gene mutations, and one that is accessible to microscopy to see cell structure and perform electrophysiology to record neuronal activity. The plan is to investigate how abnormal Torsin lipid biology affects neurons, and to relate this to the endoplasmic reticulum defects previously described in Torsin model systems. The researchers will also test whether manipulation of lipid enzymes overcomes neuronal defects of Torsin dysfunction. These experiments are important for the field to know whether lipid regulation by Torsins is relevant in neurons. It is also vital to build a cloud of mechanistic information around Torsin regulated lipid biology in order for the field and industry to be confident that lipid metabolism is indeed a key target for DYT1 dystonia, and determine whether lipid biology is important broadl

Mahlon DeLong Young Investigator Award

Deriving Transcriptional Signatures in X-linked Dystonia-Parkinsonism through Integrative Genomic Studies
Aloysius Domingo, MD, PhD, Massachusetts General Hospital

X-linked dystonia-parkinsonism (XDP) is a degenerative neurological movement disorder characterized by symptoms of dystonia in combination with symptoms of parkinsonism (tremors, bradykinesia, rigidity, balance instability, shuffling gait). It is believed to be caused by DNA changes in the TAF1 gene. XDP affects Filipino men almost exclusively. Women may be carriers but rarely become symptomatic. Only about 500 patients have been documented, and experts believe XDP is under-reported. The goal of Dr. Domingo’s project is to clarify the genetic architecture of XDP and begin to understand the brain pathways and networks that become abnormal as a consequence of the causative mutation. Improved treatment options are urgently needed, and the disease mechanisms in XDP may harbor clues into the mechanisms of other forms of dystonia and parkinsonism.

Accelerating Research & Inspiring Hope

The Dystonia Medical Research Foundation (DMRF) has served the dystonia community since 1976. Join us in our global effort to find a cure.