2014 Annual Research Grants

  • 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 Fuchs, 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.