Brain TorsinA and childhood-onset Dystonia

Summary

Principal Investigator: Pullanipally Shashidharan
Affiliation: Mount Sinai School of Medicine
Country: USA
Abstract: DYT1 dystonia is a potentially disabling hyperkinetic movement disorder characterized by sustained or repetitive involuntary muscle contractions and/or abnormal postures. The disorder is caused by a three base pair in-frame deletion in the DYT1 gene resulting in the loss of a glutamic acid residue at position 302/303 in torsinA. In our laboratory we have generated two transgenic mouse models that overexpress human mutant torsinA and develop an abnormal phenotype. The first was generated using a rat neuron-specific enolase promoter and the second a mouse DYT1 promoter (see preliminary data). Interestingly, behavioral alterations develop at approximately 3 weeks, and only 40% of transgenic mice exhibit an abnormal phenotype, a pattern similar to what is seen in human DYT1 dystonia. The basis of why some animals exhibit an abnormal phenotype and others do not is not known. We have shown that dopamine levels are reduced and extracellular glutamate levels are increased in the striatum of transgenic mice. Furthermore, yeast two-hybrid screening identified two important torsinA interacting proteins (TAIP), TAIP1 is implicated in the neurotransmission. Based on the studies performed on our current transgenic model and preliminary data obtained, there is enough evidence suggesting an alteration in neurotransmission, which could underlie the pathophysiology of DYT1 dystonia. In this proposal we will 1) Investigate neurochemical and ultra-structural changes in transgenic mouse models;2) Investigate the neuroanatomical changes by unbiased stereology to determine the underlying pathology in the two DYT1 transgenic mouse models;3) Determine the role of TAIP1 in neurotransmission and the effect of torsinA mutation on this function;and 4) Investigate the effect of crossing TAIP1 knockout mice with DYT1 transgenic mice. The long-term goals are to delineate the pathophysiology and develop novel therapeutic agents and ultimately find a cure for this highly debilitating disorder in children. PUBLIC HEALTH RELEVANCE: The purpose of this investigation is to understand the basis of childhood onset dystonia caused by a mutation in DYT1 gene mapped to human chromosome 9. The studies proposed in this application are expected to advance our knowledge of underlying pathophysiology of this syndrome and will lead to development of novel therapies for treatment and possible cure for this highly debilitating condition in affected children.
Funding Period: ----------------2001 - ---------------2013-
more information: NIH RePORT

Top Publications

  1. pmc Regulation of DYT1 gene expression by the Ets family of transcription factors
    Ioanna A Armata
    Department of Neurology, Laboratory of Developmental and Molecular Hepatology, Mount Sinai School of Medicine, New York 10029, USA
    J Neurochem 106:1052-65. 2008
  2. pmc Cortically evoked long-lasting inhibition of pallidal neurons in a transgenic mouse model of dystonia
    Satomi Chiken
    Division of System Neurophysiology, National Institute for Physiological Sciences and Department of Physiological Sciences, Graduate University for Advanced Studies, Myodaiji, Okazaki 444 8585, Japan
    J Neurosci 28:13967-77. 2008
  3. pmc The discovery of human of GLUD2 glutamate dehydrogenase and its implications for cell function in health and disease
    Pullanipally Shashidharan
    Department of Neurology, Icahn School of Medicine at Mount Sinai, Box 1137, One Gustave L Levy Place, New York, NY, 10029, USA
    Neurochem Res 39:460-70. 2014
  4. pmc Dysregulation of striatal dopamine release in a mouse model of dystonia
    Li Bao
    Department of Physiology and Neuroscience, NYU School of Medicine, New York, NY 10016, USA
    J Neurochem 114:1781-91. 2010
  5. doi Behavioural and pharmacological examinations in a transgenic mouse model of early-onset torsion dystonia
    Nikola Lange
    Institute of Pharmacology and Toxicology, Department of Veterinary Medicine, Freie Universitat Berlin, Koserstr 20, 14195 Berlin, Germany
    Pharmacol Biochem Behav 97:647-55. 2011
  6. pmc Modulation of the basal ganglia dopaminergic system in a transgenic mouse exhibiting dystonia-like features
    Dimitra Giannakopoulou
    Laboratory of Human and Animal Physiology, Department of Biology, University of Patras, 26500 Patra, Greece
    J Neural Transm 117:1401-9. 2010
  7. pmc Reduced pallidal output causes dystonia
    Atsushi Nambu
    Division of System Neurophysiology, National Institute for Physiological Sciences and Department of Physiological Sciences, Graduate University for Advanced Studies Okazaki, Japan
    Front Syst Neurosci 5:89. 2011

Scientific Experts

  • Atsushi Nambu
  • Nikola Lange
  • Pullanipally Shashidharan
  • Li Bao
  • Dimitra Giannakopoulou
  • Ioanna A Armata
  • Satomi Chiken
  • Andreas Plaitakis
  • Jyoti C Patel
  • Pullani Shashidharan
  • Panagiotis Giompres
  • Ruth H Walker
  • Margaret E Rice
  • Ada Mitsacos
  • Ioanna Armata
  • Natarajan Balasubramaniyan
  • Meenakshisundaram Ananthanarayanan

Detail Information

Publications7

  1. pmc Regulation of DYT1 gene expression by the Ets family of transcription factors
    Ioanna A Armata
    Department of Neurology, Laboratory of Developmental and Molecular Hepatology, Mount Sinai School of Medicine, New York 10029, USA
    J Neurochem 106:1052-65. 2008
    ..Ets-like dominant negatives confirmed the Ets factors as DYT1 transcriptional activators...
  2. pmc Cortically evoked long-lasting inhibition of pallidal neurons in a transgenic mouse model of dystonia
    Satomi Chiken
    Division of System Neurophysiology, National Institute for Physiological Sciences and Department of Physiological Sciences, Graduate University for Advanced Studies, Myodaiji, Okazaki 444 8585, Japan
    J Neurosci 28:13967-77. 2008
    ..Long-lasting inhibition induced by cortical inputs in the internal pallidal segment may disinhibit thalamic and cortical activity, resulting in the motor hyperactivity observed in the transgenic mice...
  3. pmc The discovery of human of GLUD2 glutamate dehydrogenase and its implications for cell function in health and disease
    Pullanipally Shashidharan
    Department of Neurology, Icahn School of Medicine at Mount Sinai, Box 1137, One Gustave L Levy Place, New York, NY, 10029, USA
    Neurochem Res 39:460-70. 2014
    ..In addition, the potential role of gain-of-function of hGDH2 variants in human neurodegenerative processes will be considered. ..
  4. pmc Dysregulation of striatal dopamine release in a mouse model of dystonia
    Li Bao
    Department of Physiology and Neuroscience, NYU School of Medicine, New York, NY 10016, USA
    J Neurochem 114:1781-91. 2010
    ..Together, these data implicate compromised DA release regulation, possibly from cholinergic dysfunction, in the motor symptoms of this dystonia model...
  5. doi Behavioural and pharmacological examinations in a transgenic mouse model of early-onset torsion dystonia
    Nikola Lange
    Institute of Pharmacology and Toxicology, Department of Veterinary Medicine, Freie Universitat Berlin, Koserstr 20, 14195 Berlin, Germany
    Pharmacol Biochem Behav 97:647-55. 2011
    ..Therefore, these data do not provide clear evidence for dysfunctions of the dopaminergic system in this mouse model...
  6. pmc Modulation of the basal ganglia dopaminergic system in a transgenic mouse exhibiting dystonia-like features
    Dimitra Giannakopoulou
    Laboratory of Human and Animal Physiology, Department of Biology, University of Patras, 26500 Patra, Greece
    J Neural Transm 117:1401-9. 2010
    ..Our results show selective neurochemical changes in the basal ganglia dopaminergic system, suggesting a possible involvement in the pathophysiology of dystonia-like motor hyperactivity...
  7. pmc Reduced pallidal output causes dystonia
    Atsushi Nambu
    Division of System Neurophysiology, National Institute for Physiological Sciences and Department of Physiological Sciences, Graduate University for Advanced Studies Okazaki, Japan
    Front Syst Neurosci 5:89. 2011
    ..Thus, reduced GPi output may cause increased thalamic and cortical activity, resulting in the involuntary movements observed in dystonia...