Our Research Portfolio

Funding innovative science and research in dystonia and Parkinson’s disease is the hallmark of our grant program. The Bachmann-Strauss Foundation supports individual researchers from around the globe engaged in projects that bring us closer to the cure for these disorders.

  • Jose Miguel Bras, PhD
  • University College, Institute of Neurology
  • London, England

 

A Role for the de Novo Mutations in Parkinson's Disease

  • Great advances have been made in discovering genetic events that lead to Parkinson's disease. This study will identify new genes that cause this devastating disease, helping to understand how the disorder starts and possibly leading to improved therapeutic approaches to slowing or even stopping the development of the disease.

 

  • Edward Burton, MD, DPhil, MRCP(UK)
  • University of Pittsburgh
  • Pittsburgh, Pennsylvania

 

Generation of Torsin 1 Knockout Zebrafish

  • The most common genetic form of dystonia, DYT1 dystonia is caused by a change in a gene that carries the instructions necessary for brain cells to make a protein called torsin. Using the zebrafish that makes a protein very similar to human torsin, this research will use the torsin knockout model to determine what torsin does in the brain, and to understand how this goes wrong in DYT1 dystonia. The ultimate goal is to develop new drug treatments for dystonia.

 

  • Mark Edwards, PhD, MRCP(UK)
  • University College, Institute of Neurology
  • London, England

 

rTMS for the Treatment of Musician's Dystonia

  • Musician's dystonia causes involuntary posturing of the affected hand. It has been suggested that involuntary movements develop because inappropriate motor memories that incorporate unwanted actions are formed during music practice under conditions of high anxiety and stress. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique which has been shown to influence motor memory retention/consolidation. This study will explore whether rTMS given to patients during active performance of movements that induce dystonia can reduce or abolish the "motor memory" responsible for the abnormal hand posturing.

 

  • Alfred Goldberg, PhD
  • Harvard Medical School
  • Cambridge, Massachusetts

 

Role of Nedd4 Activity in Protection Against Alpha-synuclein Accumulation and Parkinson's Disease

  • Studies have established that the build up of a-synuclein in dopaminergic neurons is a critical contributor in the development of Parkinson's disease. Research indicates that Nedd4 modifies a-synuclein content and its toxicity. This work will test whether it may be possible to enhance Nedd4 activation as a possible therapeutic approach to slow or prevent Parkinson's disease progression in neurons. Such experiments could provide a strong rationale for searching for drugs that bind to this domain and prevent to accumulation of a-synuclein.

 

  • Henry Houlden, PhD, MRCP(UK)
  • University College, Institute of Neurology
  • London, England

 

Neuodegeneration with Brain Iron Accumulation (NBIA): Gene Discovery and Characterization

  • Neurodegeneration with brain iron accumulation (NBIA) refers to a group of inherited neurodegenerative diseases characterized by progressive, severe dystonia, parkinsonism. This project seeks to identify and characterize novel genetic causes of NBIA using a set of powerful, complementary genetic techniques. The goal is to accelerate understanding of dystonia at the molecular level and to pave the way for the development of new treatments.

 

  • Rachel Saunders-Pullman, MD, MPH**
  • Beth Israel Medial Center
  • New York, New York

 

Phenolypic Spectrum of GNAL and THAP1 Mutation Dystonia

  • For those with a known genetic etiology, such as dystonia due to DYT1 and DYT6 mutations, information about treatment response, genetic counseling information have been studied. However, in the case of DYT6, the range of features associated with mutations is not well understood. This project will address the clinical features associated with this mutation and hopefully will lead to a better understanding and treatment for dystonia, and will also guide research in understanding the basic mechanisms and developing a cure for this form of dystonia.

 

  • Terrence J. Sejnowski, PhD
  • University of California, San Diego
  • San Diego, California

 

Objective Quantification of Phenotypic Expression in Cranial Dystonia

  • The goal of this study is to evaluate computer-aided video processing of facial muscle activity in cranial dystonia. Although clinicians have become adept at treating cranial dystonia, objective measures of symptom severity and frequency have lagged behind. Ultimately, it is hypothesized that advances in video-processing software can be used for assessing more broadly defined facial dyskinesias, and its spatiotemporal resolution will also facilitate linking pathological patterns of muscle activity to underlying pathophysiology.

 

  • Philip Starr, MD, PhD*
  • University of California, San Francisco
  • San Francisco, California

 

Cordial Phase-Amplitude Couling in Patients with Generalized Dystonia

  • The aim of this work is to understand cortical function in dystonia by studying patients undergoing awake neurosurgery. This study will investigate the cordial activity of patients with generalized dystonia. Deep brain stimulation (DB) is an efficient therapeutic treatment for movement disorders during which brain structures are stimulated electrically to alter the brain activity causing abnormal movement. To improve and develop safer and simpler therapeutic strategies, it is important to better understand the pathophysiology of dystonia, especially at the cordial level.

 

  • Peter Vangheluwe, PhD** (funded through The Michael J. Fox Foundation)
  • KU Leuven
  • Leuven, Belgium

 

Functional Characterization of ATP13A2, a P-Type Transport ATPase

  • The discovery of several genetic risk factors and progress on their cell-biological role significantly impact understanding of Parkinson's disease. Strong genetic evidence indicates that mutations in ATP13A2 in Parkinson's disease susceptibility locus lead to the Kufor-Rakeb syndrome (KRS), a severe early-onset autosomal recessive form of Parkinson's disease with dementia. However, the molecular properties of ATP13A2 remain unexplored. Uncovering its cell-biological function and role in neurodegeneration and dementia require the identification of the transported substrate. Transporters are implicated in a variety of human disorders and often, these are considered potential drug targets.

 

  • Nicholas Wood, PhD, **MRCP(UK)
  • University College, Institute of Neurology
  • London, England

 

Using Genetic to Understand Dystonia: Characterization of Effect of Mutations in AN03 and Exome Sequencing in Familial Dystonia

  • Exome sequencing is a relatively new technique that involves reading the most important parts of an individual's genetic code all in one go. Using this technique to identify mutations in the novel gene, ANO3, as the cause of a subset of cases of focal dystonia, the work will investigate the means by which mutations in this gene might lead to dysfunction at the cellular level, and how such dysfunction could be linked to the development of the abnormal movements seen in dystonia.

 

* The Dorothy Feiss Scientific Research Grant

** Jake’s Ride for Dystonia Research Grant

  • William Dauer, MD
  • University of Michigan
  • Ann Arbor, Michigan

 

TorsinB; Essential Role in Disease Pathogenesis and Animal Modeling of DYT1 Dystonia

  • DYT1 dystonia is a neurodevelopmental disease caused by a deletion in the Tor1, a gene encoding torsinA. The lab has developed a model DYT1 dystonia with overt dystonia-like movements and identified TorsinB as a powerful modifier for the torsinA dysfunction that causes abnormal twisting movements. By dissecting the role of torsinB in contributing to abnormal movements and using this information to develop a novel model, there is the potential to transform research in DYT1 dystonia.

 

  • Veronique VanderHorst, MD, PhD**
  • Beth Israel Deaconess Medical Center
  • Boston, Massachusetts

 

Cholinergic Spinal Interneurons Mediating Dystonic Phenotypes

  • The neural substrate that mediates the twisting movements so characteristic in various types of dystonia is not understood fully. Recently, technology has become available that allows the anatomical and functional dissection of the different cell types in the higher centers of the brain and motor neurons. To gain insight in the role of cholinergic neurons in various types of dystonia, a novel technology called Design Receptors Exclusively Activated by Designer Drugs (DREADD) will be used in combination with high speed video analysis, kinematics and chronic EMG recording to measure dystonic muscle activity. This work has the potential to help in developing more precise and powerful intervention strategies for dystonia.

** Jake’s Ride for Dystonia Research Grant

  • M. Angela Cenci, MD, PhD
  • Professor, Experimental Science
  • Director, Basal Ganglia Pathophysiology Laboratory
  • Lund University
  • Lund, Sweden

 

Neurivascular coupling and flow-metabolism dissociation in a rat model of L-DOPA induced dyskinsia

  • For the first time, brain-imaging methods similar to those used in human patients will be adapted to the rat. The experimental model will allow the lab to devise new pharmacological treatments targeting the abnormal reactions of cerebral microvessels in L-DOPA-induced dyskinesia. Defining both the mechanisms and the consequences of an altered regulation of rCBF in a rat model of L-DOPA-induced dyskinesia will lead to the identification of novel treatments that can reduce the development of dyskinesia by stabilizing the brain microvasculature.

 

  • C. Savio Chan, PhD
  • Assistant Professor, Department of Physiology
  • Northwestern University
  • Chicago, Illinois

 

Physiological Genomic Dissection of Globus Pallidus Neurons in hMT1Mice

  • Muscle movement is controlled by a brain circuit called the basal ganglia, and improper functioning in this motor switchboard leads to movement disorders, such as dystonia - a debilitating neurological movement disorder characterized by repetitive or sustained involuntary muscle contractions that force the body to twist into awkward, irregular postures. By using a genetic animal model of dystonia, Dr. Chan will study the abnormalities of GPe neurons at a cellular and molecular level. By measuring the activity and genetic content of these cells we will begin to pinpoint how and why these cells are different in disease states.

 

  • Ruth Chia, PhD
  • Visiting Fellow, Laboratory of Nemogenetics
  • National Institute in Aging
  • Bethesda, Maryland

 

shRNA kinome screen for the identification of kinase regulators of LRRK2

  • Mutations in Leucine-rich repeat kinase (LRRK2) cause a significant proportion of inherited Parkinson's Disease (PD). LRRK2 mutation cases are very clinically similar to non-inherited, or sporadic, PD telling us that clues from inherited disease might help develop new therapies for several types of PD. However, there are significant gaps in our knowledge about LRRK2. Addressing these will help to advance towards therapeutics. This project aims to identify how LRRK2 is controlled by other kinases. This will be invaluable knowledge especially when designing LRRK2-specific therapeutics.

 

  • Ann M. Graybiel, PhD
  • Professor, McGovern Institute for Brain Research
  • Department of Brain and Cognitive Sciences
  • Massachusetts Institute of Technology
  • Cambridge, Massachusetts

 

Striosomc-matrix function as a window into dystonia, L-DOPA induced dyskinesia, and Parkinson's Disease

  • Dysfunction of the striatum and dopamine neurons is well-known causes of Parkinson's Disease, dystonia, and related disorders. Intriguingly, another prominent striatal feature has also been linked to dystonia, L-DOPA induced dyskinesia and animal models of Parkinson's disease. Dr. Graybiel proposes to record from identified striosome and matrix neurons of rodents during behavioral tasks designed to engage the striatal compartments differentially. The results are expected to illuminate the functional differences between striosomes and matrix, thus opening a new window in the study and treatment of dystonia, L-DOPA induced dyskinesia, Parkinson's disease and related disorders.

 

  • Diane Ruge, PhD
  • Institute of Neurology
  • London, England

 

Plasticity in deep brain stimulation treated dystonia‐patients, a functional MR Imaging stud

Deep brain stimulation (DBS) can be a very effective treatment for certain types of dystonia. Dr. Ruge's work will look at two aspects of DBS peculiar to dystonia. The first is that the response to DBS often takes several weeks to reach maximum benefit. The second is that some people have been implanted for several years. If DBS is turned off after many years, symptoms in some people may not reappear for many days or even weeks. Others, however, regain their symptoms immediately. Researchers suspect that in them the DBS is having some long-term effect on how the brain's activity is organized, maybe gradually changing it back to the pattern seen in healthy volunteers without dystonia. By combining this information with details of exactly where the electrodes are placed in the brain and what stimulation parameters are being used, we will be able to make some predictions about how to optimize and prolong the DBS effect.

 

  • Pullani Shashidharan, PhD
  • Department of Neurology
  • Mount Sinai School of Medicine
  • New York, New York

 

Phenotypic and neurochemical characterization of a rat (knockin) model of DYT1 dystonia

  • Dystonia is a neurological syndrome characterized by abnormal involuntary movements causing twisting and turning of body parts and can result in contorted postures. Among the various forms of dystonia the early onset dystonia (DYTl) is associated with a deletion mutation in the TORI A gene located on chromosome 9, which codes for a protein called torsinA, whose cellular function is unknown. Symptoms of the disease usually start in the leg, mostly during adolescence, and spread to other body parts, and the subject becomes wheel-chair bound. Dr. Sashidharan's current project will investigate the behavioral, neurochemical and biochemical characteristics of the (knockin) rat model.

 

  • Ana Westenberger, PhD
  • Postdoctoral Fellow, University of Luebeck
  • Luebeck, Germany

 

New insights into the genetics and molecular pathways of XDP

  • X-linked dystonia-parkinsonism (XDP; DYT3) is a neurodegenerative movement disorder inherited in an X-linked recessive manner, due to a genetic founder effect, only in individuals of Filipino ancestry. XDP represents a unique model system to study molecular, cellular, neurophysiological and neuroanatomical mechanisms causing these two important movement disorders. Dr. Westenberger will use three parallel approaches. The results of this study will elucidate the basis of neurodegeneration in XDP and potentially explain cellular pathways that are involved in the occurrence of dystonia and parkinsonism, and suggest specific therapeutic approaches in future studies.

 

  • Movement Disorder Fellowship:

 

  • Jeff Waugh, MD
  • Massachusetts General Hospital

 

  • Jeff Waugh, MD was awarded the Silverman Family Fellowship for specialty training in movement disorders, important to become an academic pediatric neurologist. Dr. Waugh’s fellowship began at Massachusetts General Hospital (MIT) in 2012. The goal of his work is to gain expertise in the methodology, experimental design, and analysis of brain imaging techniques in movement disorders. He will be co-mentored by two distinguished MIT professors: Nutan Sharma, MD, PhD, Associate Professor of Neurology and Director, Dystonia Clinic in Movement Disorders Program, and Anne J. Blood, PhD, Assistant Professor of Psychiatry and Director, Mood and Motor Control Laboratory.

 

2012 Special Program Grants

 

  • Ellen Hess, PhD
  • Professor, Department of Pharmacology
  • Emory University School of Medicine
  • Atlanta, Georgia

 

Anti-Dystonia Drug Discovery Program

  • The Bachmann-Strauss Scientific Advisory Board has announced that the Foundation will continue to fund the, headed by. "My general goal is to understand the pathomechanisms of dystonia by examining the underlying anatomical, physiological and biochemical substrates of the disorder by creating and manipulating mouse models. This strategy allows us to induce or ameliorate motor dysfunction in the context of an intact nervous system revealing potential targets for therapeutics," explained Dr. Hess. For example, her team is currently using behavioral and cellular pharmacology to understand the cellular mechanisms that give rise to hyperactivity. Continuing her Bachmann-Strauss funded research studies, the objective of Dr. Hess's research is to identify drugs that can either move directly into clinical trial or be put forward for product development by a biotechnological or pharmaceutical company. The drug screening protocol created in the first phase of her research has transitioned to the testing of new compounds to alleviate dystonia symptoms in mice. Looking ahead, the Anti-Dystonia Drug Discovery Program plans to make drug screening more widely available to facilitate preclinical testing of novel anti-dystonia compounds.

 

  • H.A. Jinnah, MD, PhD
  • Professor, neurology, human genetics and pediatrics,
  • Emory University
  • Atlanta, Georgia

 

Dystonia Coalition iPS Resource

  • The goal of Dr. Jinnah’s project is to develop a resource for the collection of skin samples for making fibroblast cultures for dystonia, to create stem cells from these fibroblasts to share with dystonia investigators, and to begin to examine the defects in these cells after they are converted into dopamine neurons. As these cells are made from skins samples of dystonia patients, they will contain the genetic defects responsible for the disorder.

 

  • Cristopher Bragg, PhD
  • Assistant Professor of Neurology
  • Massachusetts General Hospital
  • Boston, Massachusetts

 

Generating Isogenic Dystonia iPS Cell lines with Custom TALE Nucleases

  • Dr. Bragg’s project will generate iPSCs to different genetic causes of dystonia by turning normal cells into cells with dystonia mutations with TALE nucleases. Essentially they will be able to create iPSCs to any genetic form of dystonia using TALE technology. Dr. Bragg will also collaborate with the Jinnah laboratory in developing and comparing the different dystonia iPSC models. Directly comparing TALE nuclease -generated iPSC lines to ones generated by reprogramming patient fibroblasts can provide a lot of useful information.

SPECIAL PROGRAMS:

 

The Anti-Dystonia Drug Discovery Program, under the direction of Ellen Hess, PhD, Emory University School of Medicine, completed a second year of research studies to identify drugs that can either move directly into clinical trial or be put forward for product development by a bio-technology or pharmaceutical company. The drug screening protocol created in the first phase of development has transitioned to the testing of new compounds to alleviate dystonia symptoms in mice. The Bachmann-Strauss Foundation continues to fund this important project and is enthusiastic about the potential outcomes.

 

The Michel J. Fox Foundation received a second year grant for Dr. Danna Jennings, principal investigator, to explore the function of the neurotransmitter glutamate, and to evaluate the impact of glutamate antagonists, medications with the potential of reducing dyskinesia in Parkinson’s disease patients. This study has strong potential for developing novel medications that could benefit both dyskinesia and dystonia symptoms. Bachmann-Strauss has partnered with the Michael J. Fox Foundation for many years and continues to be their lead partner in the study of dyskinesia.

 

GRANTS:

 

  • Joshua Berke, PhD
  • University of Michigan
  • Ann Arbor, MI

 

Real-time monitoring of striatonigral and striatopallidal cells in mice with levodopa induced dyskinesias

  • Prolonged levodopa therapy for Parkinson's disease frequently results in uncontrolled movements called levodopa-induced dyskinesias (LIDs). The brain changes responsible for LIDs are currently unknown. Using state-of-the-art techniques to monitor and manipulate individual neurons, Dr. Berke will test the hypothesis that one specific subtype of basal ganglia cell shows altered activity leading to LIDs. The results are expected to be extremely helpful for the generation of new therapies that either prevent or suppress LIDs.

 

  • Xandra Breakefield, PhD, and Naoto Ito, PhD
  • Massachusetts General Hospital
  • Cambridge, MA

 

Exploring the role of Dropsophila dtorsin gene in regulating dopamine metabolism

  • This study aims to clarify the role of torsin in dopamine metabolism by evaluating dtorsin-deficient flies that the researchers created. Because Drosophila (fruit fly) has one dtorsin gene similar to human DYT1, which is defective in early onset dystonia, the research should aid in evaluating the potential usefulness of drug modulation of dopaminergic neurotransmission in DYT1 patients.

 

  • Michelle Ehrlich, MD 
  • Mount Sinai School of Medicine
  • New York, NY

 

Regulation of TorsinA in a knockin model of DYT6 dystonia

  • DYT6 is one of the inherited dystonias, caused by one of several mutations that have been identified in the gene THAP1, which is present in the developing and adult mouse brain. This study will create a genetically accurate mouse model of DYT6, in which regulation and levels of THAP1 will be under normal control in order to determine if this mutation alters the regulation of other genes that are known to play a role in dystonia.

 

  • Phyllis Hanson, MD, PhD
  • Washington University School of Medicine
  • St. Louis, MO

 

Reversing the mislocalization of TorsinA

  • This study builds on Dr. Hanson’s discovery that localization is a property of TorsinA regulated in the cell and by earlier findings showing that TorsinA is frequently mislocalized. The new study will design a screen to identify new genes that regulate TorsinA activity by controlling where it is located in the cell, looking for new candidates and pathways that may be targets for therapeutic intervention in dystonia.

 

  • Christine Klein, MD

  • University of Luebeck
  • Germany

 

Application of next generation sequencing to identify a new dystonia gene

  • Using the genomes of a family with eight members affected by spasmodic dysphonia, the study seeks to identify a new dystonia gene by applying genome-wide linkage analysis and the latest sequencing techniques to be followed by mutational analysis of the newly identified gene in other dystonia patients. By identifying a novel genetic cause of dystonia, the study may explain many forms of the disease and lead to new therapies.

 

  • Antonio Pisani, MD

  • Fondazione Santa Lucia
  • Rome, Italy

 

Evaluating the Role of thalamic activity in the pathogenesis of dystonia

  • In his previous research into DYT1 dystonia, Dr. Pisani discovered a profound impairment in the synaptic plasticity of the striatum, a brain region involved in motor control. Dr Pisani now seeks to determine whether the aberrant synaptic plasticity of the corticostiatal pathway might lead to an imbalance with the other means of striatal cholinergic transmission, the thalamostriatal pathway. These experiments might have relevant implications for the pathophysiology of dystonia.

 

  •  Jan-Willem Taanman, PhD
  • Institute of Neurology
  • University College London
  • England

 

Converting laboratory-created stem cells into rapid-onset dystonia-parkinsonism neuronal cells

  • A major barrier to the study of dystonia and Parkinson’s in the laboratory has been the inaccessibility of neuronal cells from patients. Now that there is a new technique for creating stem cells, Dr. Taanman will attempts to convert stem cells into neuronal cells affected by rapid-onset dystonia-parkinsonism. This work can open the door to a thorough investigation of the disease mechanism of rapid-onset dystonia-parkinsonism and potentially screen for drugs.

 

  • Enrique Torre, PhD

  • Emory University School of Medicine
  • Atlanta, GA

 

The Impact of Mutant TorsinA on the Axon Function

  • More than 50% of carriers of mutant TorsinA never manifest early onset torsin dystonia (DYT1), but recent imaging studies suggest a deficit in the quality or number of fibers in the axon (the projection of a nerve cell that conducts electrical impulses away from the neuron’s cell body or soma). Dr. Torre will investigate the hypothesis that neurons become vulnerable to stress when expressing a mutated TorsinA, leading to a dysfunctional and/or or dystrophic axon unable to sustain normal synaptic communication or plasticity. These studies will help to understand the role of TorsinA in the normal function of axons and the connections they establish and to design better targeted treatments.

 

Aziz Ulug, PhD

  • The Feinstein Institute for Medical Research
  • Manhasset, NY

 

Determination of Brain Pathways Involved in Dystonia Using a Mouse Model

  • Employing a novel experimental approach to validate and expand upon the findings of the human imaging study conducted in DYT1 carriers of dystonia, Dr. Ulug will image DYT1 knockin mice in vitro and ex vitro in order to visualize the white matter pathways that pass through the abnormal brain regions identified in his earlier scans. This study will allow for the direct assessment of the effect of the DYT1 mutation on the structure and function of brain motor pathways.
  • Karel Liem, MD, PhD
  • Yale School of Medicine
  • New Haven, Connecticut

 

Characterization of a Novel Mouse Mutant of the DYT4-Associated Gene Tubb4a

  • Tubb4a has been recently identified as a gene associated with the hereditary dystonia, DYT4. The neural processes that are disrupted by Tubb4a mutations that lead to dystonia are unknown. Mouse models of neurological diseases have been vital for understanding the pathophysiology of the disorders. In a genetic screen, we have generated a mouse mutant of Tubb4a that develops a dystonic phenotype. We would like to better understand the neural circuits and cellular pathways that are disrupted in dystonia. Tubb4a is expressed by specific cell populations within the brain and spinal cord and we will use mouse genetics to better characterize and identify the neural cells disrupted in our mouse. This will lead to better understanding of DYT4 and other dystonias and be potentially informative for the rational development of therapeutic treatments.

 

  • Roy Vincent Sillitoe
  • Baylor College of Medicine
  • Houston, Texas

 

Determining the Trigger for Cerebellar Dystonia

  • Dystonia is a devastating movement disorder that causes the muscles to contract uncontrollably. Regardless of whether it attacks small muscles in a single body part or large muscles in several body parts, defects in brain communication are always involved. Studies in humans and experiments in animal models have discovered that communication problems in a brain region called the cerebellum can cause the disease. However, how defective communication in the cerebellum causes dystonia is far from clear. The goal of this proposal is to determine the mechanisms that trigger cerebellar miscommunication in dystonia. Towards this goal, we devised a mouse genetic strategy to precisely manipulate the function of specific connections called synapses. Synapses generate nerve signals that are rapidly transported between cells–in the cerebellum this process coordinates muscle contractions. Based on recent data, we hypothesized that the cerebellum may have one particular type of synapse that is extremely susceptible to dystonia pathogenesis, and therefore altering its function could be a major trigger for the disease. Remarkably, we found that altering this synapse indeed causes severe dystonia in mice, with a striking similarity to what is observed in humans with generalized limb and body dystonia. We are proposing to use this powerful model to determine how triggering erroneous cerebellar communication alters motor signaling to cause dystonia. Because we are able to manipulate developing and adult synapses independently, we will also determine whether childhood onset and adult onset forms of the disease can emerge by altering the same synapses, but at different times. A better understanding of how cerebellar synapses initiate dystonia will provide new opportunities for targeting defective circuits with therapies to rewire networks and restore motor function. Our model offers an ideal strategy with which to validate potential treatments. 

 

  • Veronique VanderHorst, MD, PhD
  • Beth Israel Deaconess Medical Center
  • Boston, Massachusetts

 

Cholinergic Spinal Interneurons Mediating Regional Dystonic Phenotypes

  • The neural circuitries that mediate the twisting movements so characteristic for dystonia are not fully understood. This is especially true for complex brainstem and spinal regions that form a relay between higher centers in the brain and motoneurons in the spinal cord and brainstem, the neurons that mediate the abnormal muscle activity so characteristic for dystonia. Insight in the function and organization of these circuitries is relevant as these circuitries themselves may be involved in various types of dystonia or could form potential new targets for intervention. In our currently funded project we are using a novel technology to induce a dystonia-like response in mice by activating small clusters of cholinergic neurons in the spinal cord. This novel technology is called Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology, and allows to selectively modulate subtypes of neurons in complex regions. It makes use of mutated receptors which can be built into selected groups of neurons. These neurons can then be reversibly activated by a designer drug that does not affect other neurons. Following acute activation of spinal cholinergic interneurons, dystonia-like phenotypes are elicited that involve discrete parts of the body. The region of the body involved reflects the unique connections of clusters of cholinergic neurons. The question now arises whether these changes persist following chronic activation and whether additional changes occur following withdrawal of chronic activation. Our goal is to address these questions in this new proposal. The results of this study will give us insight in the degree of plasticity that may occur in this system, a phenomenon important for dystonias. A role of spinal cholinergic interneurons in dystonia will change current paradigms of dystonia research and will help to develop more precise and powerful interventional strategies for dystonia.

 

 

  • John Hardy, PhD
  • UCL Institute of Neurology
  • London, United Kingdom

 

Development of a Neuronal <odel of PANK2 Sssociated Neurodegeneration with Brain Iron Accumulation (NBIA)

  • Dystonia is a common movement disorder that can lead to sustained muscle contractions, repetitive twisting movements and abnormal postures of the trunk, neck, face, arms and legs. Neurodegeneration with brain iron accumulation (NBIA) refers to a group of inherited neurodegenerative diseases characterized by progressive, severe dystonia, parkinsonism and pyramidal signs with accumulation of iron in brain tissue. NBIA is usually very aggressive, most patients die in their late teens or early twenties and there is no effective treatment. Genetic mutations in the pantothenate kinase 2 gene (PANK2) are the commonest cause of NBIA. In order to develop a model of NBIA with a human genetic background we have developed induced pluripotent stem cells (iPS) from the fibroblasts of two NBIA patients with PANK2 mutations and a third is underway. We will differentiate the PANK2 iPS cells and matched controls into cortical and midbrain dopaminergic neurons that will provide the most comparable NBIA disease model. These cells will be characterized focusing on the key pathological features of NBIA looking at iron and tau and also investigating the mitochondrial function that may be defective in NBIA patients with PANK2 mutations. The fibroblasts, iPSC and differentiated neurons that are created from this project will be open access to other research groups. The future plan in these models will be to rescue the neuronal function of PANK2 with compounds such as Deferiprone and potentiators of mitochondrial function such as Bezafibrate and to develop other NBIA neuronal lines to investigate overlapping pathways that lead to this phenotype.

 

  • Narayanan Nandakumar, MD, PhD
  • University of Iowa
  • Iowa City, Iowa

 

Serotonin Neuron and Dyskinesias in Parkinson's Disease

  • One devastating side effect of treatment for Parkinson’s disease is dyskinesias, or involuntarymovements that are difficult to control. The mechanism of dyskinesias in Parkinson’s disease is unknown. This proposal studies the basic neural circuitry of dyskinesias with the hope of finding newtreatments for this difficult clinical problem. Specifically, we use cutting-edge techniques in powerful animal models to systematically investigate how neurons that contain the neurotransmitter serotonincontribute to dyskinetic movements. Although these neurons project strongly to brain areas affected by Parkinson’s disease, and drugs targeting these neurons can affect dyskinesias, they have never been studied in this disease. Our team has a strong track of neuronal record in awake, freely moving rodents, and we have unique tools to specifically and selectively manipulate serotonin neurons in animal models of Parkinson’s disease. We anticipate that findings from our research could illuminate the basic mechanism of how serotonin neurons influence movement. This work is readily translatable to the clinical arena as understanding the role of serotonin neurons in movement could lead directly to new, highly targeted therapies for Parkinson’s disease and other disorders of movement.

 

  • Louis Ptacek, MD
  • University of California, San Francisco
  • San Francisco, California

 

Generation of PRRT2 Knock-Out Model of Paroxysmal Kinesigenic Dyskinesia

  • Paroxysmal kinesigenic dyskinesia (PKD) is an episodic movement disorder manifest by child onset episodes of choreoathetosis and dystonia that are precipitated by sudden voluntary movements. Affected patients can have hundreds of attacks per day. We’ve also shown that benign infantile convulsions are a part of the phenotype but these have typically resolved and are sometimes forgotten once a patient is experiencing hundreds of movement disorder attacks each day. We cloned the gene for a related disorder, Paroxysmal non-kinesigenic dyskinesia (PNKD), and shown the encoded protein is a novel synaptic protein regulating exocytosis. The mouse model we generated recapitulates the human phenotype. More recently identified and cloned the gene causing PKD. Like the gene causing PNKD, the PKD gene encodes a novelprotein of unknown function. We propose to generate a mouse model of PKD so that we can study the function of the wild-type PKD protein (PRRT2) and study pathophysiology in vivo. Greater understanding of PRRT2 function and PKD pathophysiology may ultimately lead to better diagnosis and treatment of paroxysmal dyskinesias. In addition, better understanding of dopamine signaling and dysregulation in PKD may lead to better understanding and treatment of other movement disorders like Parkinson’s Disease.

 

  • Tatiana Fucks, PhD
  • Icahn School of Medicine at Mount Sinai
  • New York, New York

 

Gene Discovery in Familial Cervical Dystonia

  • The genetic basis of most primary dystonia remains unknown and pathogenic mechanisms are poorly understood. Cervical Dystonia (CD) is one of the most common forms of primary focal dystonia with a prevalence estimated at 30/100,000 in the general population. Treatment is incomplete and empiric. This grant is focused on finding a genetic cause for CD. We will use an innovative, powerful technique to screen all genes in 10 unrelated familial CD patients to develop a list of potential causative genes. We will screen these genes in other CD patients to identify CD causative gene (s) among these patients. This research will uncover a new causative gene for CD, contribute to our understanding of disease mechanism and provide a basis for the development of new therapies.

 

  • Brian Mathur, PhD
  • University of Maryland School of Medicine
  • Baltimore, Maryland

 

Serotonergic Control of Corticostriatal Synapses in L-DOPA- Induced Dyskinesia

  • Parkinson’s disease (PD) is a neurodegenerative disease affecting roughly 10 million people worldwide. The cardinal symptoms of the disease, tremor, muscle rigidity and slowness of movement, can be effectively treated by the dopamine replacement therapeutic L-DOPA, which serves to replenish dopamine levels in an area of the brain, called the striatum, which is critical to normal motor function. L-DOPA is very effective in alleviating PD motor symptoms in the initial 5-10 years of use. After this period, however, debilitating abnormal involuntary movements known as dyskinesias develop as a side effect that severely hamper patient quality of life. Mechanistic data underlying dyskinesia development implicate dysfunction in two distinct neurotransmitter systems within the striatum; the serotonin system and the glutamate system. We have recently discovered that serotonin directly modulates glutamate release into the striatum, and this is the primary means by which serotonin controls striatal output. Because dysregulation of these striatal glutamatergic synapses is thought to contribute to both the symptoms of PD and dyskinesia, we hypothesize that aberrant serotonin control of glutamate release contributes to the development of L-DOPA-induced dyskinesia. Using state-of-the-art optogenetic, electrophysiological, and behavioral methods in a mouse model of PD, this study should provide a significant advance in the mechanistic understanding of dyskinesia, paving the way toward extending the therapeutic window of dopamine replacement therapy.

 

  • Aiqun Li, PhD
  • The New York Stem Cell Foundation
  • New York, New York

 

Development of an Automated Process to Obtain Reproducible Panels of Purified Dopamine-Producing Cells for Modeling Parkinson’s Disease

  • The recent discovery of induced pluripotent stem (iPS) cells provides a novel platform to evaluate how genetic and environmental risk factors contribute to Parkinson’s disease (PD) at the cellular level. Our group analyzed whether iPS cell-derived midbrain dopamine-producing (mDA) neurons generated from controls differed from PD patients, including a unique pair of identical twins (one has PD, the other does not) carrying the missense mutation of glucocerebrosidase (GBA N370S). We demonstrated that PD twin-derived mDA neurons had elevated alphasynuclein, decreased GBA activity, low dopamine level and up-regulated monoamine oxidase. These results were obtained using a limited number of cell lines and we must now determine whether the phenotype is specific to these samples, to those affected by PD who have a GBA mutation, or the broader PD community. To extend our study we must include large numbers of cell lines that are prohibitive using standard manual techniques due to scale and susceptibility to user based variation. Critical to this extended evaluation is access to relevant cell lines and systems to precisely differentiate and manipulate the cells under reproducible conditions. Each step of this process from patient to iPS cell to mDA neuron represents opportunities for variation that could affect the integrity of the phenotype-based readouts. The NYSCF Research Institute already established the ability to automate iPS cell reprogramming and differentiation and this reduces sources of variation introduced during manual procedures. We propose to extend these efforts to include a step for isolating pure mDA neurons and evaluate the merit of our previous studies across a large number of PD and control cell lines. A critical value of this proposal is that the automation protocols can be used by other researchers and it is part of NYSCF’s mission to make all resources available to other researchers interested in studying PD.