2012 Annual Research Grants

  • 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.