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 is expressed by specific cell populations within the brain and spinal cord and has been identified as a gene associated with the hereditary dystonia DYT4. The neural processes disrupted by Tubb4a mutations that lead to dystonia are unknown. The lab has generated a mouse mutant of Tubb4a that develops a dystonic phenotype and seeks to better understand the neural circuits and cellular pathways that are disrupted in dystonia. Researchers are using mouse genetics to better characterize and identify the disrupted neural cells. This will lead to better understanding of DYT4 and other dystonias and potentially support development of new therapies


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

Determining the Trigger for Cerebellar Dystonia

  • Defects in brain communication are always involved in dystonia. While studies have shown that communication problems in the cerebellum can cause the disease, the mechanism of this defective communication is unclear. Using mouse models, the lab is examining the mechanisms that trigger this cerebellar miscommunication. The lab’s strategy is to manipulate the function of specific connections called synapses. They hypothesize that the cerebellum may have one type of synapse that is extremely susceptible to dystonia pathogenesis. Therefore, altering its function may be a major trigger for the disease. They have found that altering this synapse causes severe dystonia in mice, with a striking similarity to what is observed in humans. This 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 of dystonia are not fully understood. Insight into these circuitries is relevant as they may be involved in various types of dystonia or could form potential new targets for intervention. The lab is using a novel technology, called Designer Receptors Exclusively Activated by Designer Drugs (DREADD), to induce a dystonia-like response in mice by activating small clusters of cholinergic neurons in the spinal cord. These neurons can then be reversibly activated by a designer drug that does not affect other neurons. Following activation, dystonia-like phenotypes are elicited. The lab is examining what changes occur following chronic activation and withdrawal of chronic activation.



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

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

  • 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 aggressive; there is no effective treatment and most patients die by their early twenties. Genetic mutations in the pantothenate kinase 2 gene (PANK2) are the commonest cause of NBIA. To produce a model of NBIA with a human genetic background, the lab developed specialized cells from NBIA patients with PANK2 mutations. The future plan in these models will be to rescue the neuronal function of PANK2 with certain compounds and to develop other NBIA neuronal lines for investigation.


  • 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 (PD) is dyskinesias, or involuntary movements that are difficult to control. This proposal studies the basic neural circuitry of dyskinesias with the hope of finding new treatments. Specifically, the lab uses cutting-edge techniques in powerful animal models to systematically investigate how neurons that contain the neurotransmitter serotonin contribute to dyskinetic movements. The research team will selectively manipulate serotonin neurons in animal models of PD. The findings could illuminate the basic mechanism of how serotonin neurons influence movement, potentially leading to new, highly targeted therapies for PD and other movement disorders.


  • 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 a movement disorder manifest by child onset episodes of choreoathetosis and dystonia precipitated by sudden voluntary movements. Benign infantile convulsions are a part of the phenotype but typically resolve and are sometimes forgotten once a patient is experiencing hundreds of movement disorder attacks each day. The team has cloned the genes causing PKD and a related disorder and generating mouse models for further study, which may lead to better diagnosis and treatment of paroxysmal dyskinesias. In addition, better understanding of dopamine signaling and dysregulation in PKD may provide insights into new treatments for 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

  • 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. The lab is using an innovative, powerful technique to screen all genes in ten 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). This research will uncover a new causative gene for CD, contribute to the 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

  • Therapeutic L-DOPA is a treatment for the symptoms of Parkinson’s disease (PD), serving to replenish dopamine levels in the striatum, an area of the brain that is critical to normal motor function. L-DOPA is initially effective in alleviating PD motor symptoms. However, after five to ten years, dyskinesias develop, hampering patient quality of life. Dyskinesia development may be linked to dysfunction in two neurotransmitter systems within the striatum: the serotonin and glutamate systems. The lab is studying how interactions between these two systems contribute to the development of L-DOPA induced dyskinesia in a mouse model of PD.


  • 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

  • Induced pluripotent stem (iPS) cells provide a novel platform to evaluate how genetic and environmental risk factors contribute to Parkinson’s disease (PD). The lab analyzed whether iPS cell-derived midbrain dopamine-producing (mDA) neurons generated from controls differed from PD patients, including a pair of identical twins (one has PD, the other does not) carrying the missense mutation of glucocerebrosidase (GBA N370S). PD twin-derived mDA neurons were found to have elevated alphasynuclein, decreased GBA activity, low dopamine level and up-regulated monoamine oxidase. The team is determining whether the phenotype is specific to these samples, to those affected by PD who have a GBA mutation, or the broader PD community.