MOLECULAR ETIOLOGY OF EARLY ONSET TORSION DYSTONIA
Principal Investigator: XANDRA OWENS BREAKEFIELD
Abstract: Torsion dystonia is one of the most common and least well understood movement disorder in humans. Affected individuals manifest contracted twisting movements and abnormal postures, which can be crippling. Early onset generalized dystonia (DYT1), the most severe of the hereditary dystonias, is caused by a dominant mutation in the T0R1A gene encoding torsinA. Genetic association studies indicate that this gene may also be involved in the more prevalent adult onset, focal dystonias. This long-standing team will focus on: identifying other genes and mutations involved in dystonia;understanding the function and potential interaction of torsinA with proteins at the cellular level;elucidating the role of torsinA in brain development;and generating conditional DYT1 mouse models which will allow identification of affected brain circuitry and neurotransmitter abnormalities, and provide preclinical models for therapeutic testing. Specifically Dr. Ozelius (Project 1) will focus on identifying genes responsible for penetrance in DYT1 and additional genes underlying non-DYT1 early onset dystonia, as well as variations in these early onset genes that may contribute to later onset dystonias. Dr. Breakefleld (Project 2) will evaluate cellular functions of torsinA and associated proteins including their role in movement of organelles during neuronal migration, processing proteins through the secretory pathway and stress responses in the endoplasmic reticulum. The emphasis of Drs. Bhide and Sharma (Project 3) will be on determining the developmental role of torsinA in neurogenesis and neuronal migration in several brain regions, including motor cortex, striatum and midbrain, and related effects on neuronal numbers, transcription factors and signaling. Drs. Standaert and Li (Project 4) will use conditional torsin-A knockout mice to identify regions of the brain and neurotransmitter systems involved in DYT1 dystonia, and test therapeutic drugs. Dr. Breakefleld will serve as Program Director (Core A). Translational relevance and access to patient information and samples will be provided through the clinical Core B under Dr. Nutan Sharma. These integrated studies capitalize on the extensive and complementary expertise of this group focused on the molecular etiology and pathophysiology of early onset dystonia.
Funding Period: 2000-01-01 - 2014-07-31
more information: NIH RePORT
- Update on treatments for dystoniaD Cristopher Bragg
Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
Curr Neurol Neurosci Rep 14:454. 2014..We will also review the current treatment approaches and suggest ways in which these therapies can be applied to individuals with dystonia. ..
- Enhanced hippocampal long-term potentiation and fear memory in Btbd9 mutant miceMark P DeAndrade
Interdisciplinary Program in Biomedical Sciences, College of Medicine, University of Florida, Gainesville, Florida, United States of America
PLoS ONE 7:e35518. 2012..Further analyses of the mutant mice will help shine light on the function of BTBD9 and its role in RLS...
- New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonismRichard L Barbano
Department of Neurology, University of Rochester School of Medicine, Rochester, NY, USA
Parkinsonism Relat Disord 18:737-41. 2012..Rapid-onset dystonia-parkinsonism (RDP) was not suspected until 3 affected children (2 male, 1 female) with presentations consistent with the disorder were recognized...
- Alteration of striatal dopaminergic neurotransmission in a mouse model of DYT11 myoclonus-dystoniaLin Zhang
Department of Neurology, School of Medicine, University of Florida, Gainesville, Florida, United States of America
PLoS ONE 7:e33669. 2012..Neuroimaging studies of DYT11 M-D patients show reduced dopamine D2 receptor (D2R) availability, although the possibility of increased endogenous dopamine, and consequently, competitive D2R occupancy cannot be ruled out...
- Improved motor performance in Dyt1 ΔGAG heterozygous knock-in mice by cerebellar Purkinje-cell specific Dyt1 conditional knocking-outFumiaki Yokoi
Department of Neurology, College of Medicine, University of Florida, Gainesville, FL 32610 0236, USA
Behav Brain Res 230:389-98. 2012..The results suggest that molecular lesions of torsinA in Purkinje cells by gene therapy or intervening in the signaling pathway downstream of the cerebellar Purkinje cells may rescue motor symptoms in dystonia 1...
- Evidence for altered basal ganglia-brainstem connections in cervical dystoniaAnne J Blood
Mood and Motor Control Laboratory, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America
PLoS ONE 7:e31654. 2012..While studies in animal models support a role for this circuitry in the pathophysiology of the movement disorder dystonia, thus far, there is only indirect evidence for this in humans with dystonia...
- Genetics of dystoniaTania Fuchs
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York 10029, USA
Semin Neurol 31:441-8. 2011..Currently, 19 loci including 10 genes have been identified for inherited dystonias. In this review, the phenotypes associated with these loci and the responsible genes will be discussed...
- Deep brain stimulation for medically refractory life-threatening status dystonicus in childrenBrian P Walcott
Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA
J Neurosurg Pediatr 9:99-102. 2012..Bilateral globus pallidus internus stimulation appears to be effective in the urgent treatment of medically refractory and life-threatening movement disorders...
- Abnormal nuclear envelope in the cerebellar Purkinje cells and impaired motor learning in DYT11 myoclonus-dystonia mouse modelsFumiaki Yokoi
Department of Neurology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Behav Brain Res 227:12-20. 2012....
- Dtorsin, the Drosophila ortholog of the early-onset dystonia TOR1A (DYT1), plays a novel role in dopamine metabolismNoriko Wakabayashi-Ito
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America
PLoS ONE 6:e26183. 2011..This dtorsin mutant line will be valuable for understanding this relationship and potentially other novel torsin functions that could play a role in human dystonia...
- Motor deficits and decreased striatal dopamine receptor 2 binding activity in the striatum-specific Dyt1 conditional knockout miceFumiaki Yokoi
Department of Neurology, College of Medicine, University of Florida, Gainesville, Florida, United States of America
PLoS ONE 6:e24539. 2011..The results suggest that the loss of striatal torsinA alone is sufficient to produce motor deficits, and that this effect may be mediated, at least in part, through changes in D2R function in the basal ganglia circuit...
- Developmental profile of the aberrant dopamine D2 receptor response in striatal cholinergic interneurons in DYT1 dystoniaGiuseppe Sciamanna
Department of Neuroscience, University Tor Vergata, Rome, Italy
PLoS ONE 6:e24261. 2011..DYT1 dystonia, a severe form of genetically determined human dystonia, exhibits reduced penetrance among carriers and begins usually during adolescence. The reasons for such age dependence and variability remain unclear...
- Cholinergic dysregulation produced by selective inactivation of the dystonia-associated protein torsinAGiuseppe Sciamanna
Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma Tor Vergata and Fondazione Santa Lucia, I R C C S, Rome, Italy
Neurobiol Dis 47:416-27. 2012..These results demonstrate a cell-autonomous effect of Dyt1 deletion on striatal cholinergic function. Therapies directed at modifying the function of cholinergic neurons may prove useful in the treatment of the human disorder...
- Motor restlessness, sleep disturbances, thermal sensory alterations and elevated serum iron levels in Btbd9 mutant miceMark P DeAndrade
Interdisciplinary Program in Biomedical Sciences and Department of Neurology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Hum Mol Genet 21:3984-92. 2012..Finally, our data argue for the utility of Btbd9 mutant mice to discover and screen novel therapeutics for RLS...
- Clinical neurogenetics: dystonia from phenotype to genotypeJeffrey L Waugh
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MA, USA Department of Neurology, Boston Children s Hospital, MA, USA Electronic address
Neurol Clin 31:969-86. 2013....
- Dopa-responsive dystonia: functional analysis of single nucleotide substitutions within the 5' untranslated GCH1 regionIoanna A Armata
Department of Neurogenetics, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, United States of America
PLoS ONE 8:e76975. 2013..The biologic significance of these 5'UTR GCH1 sequence substitutions has not been analyzed...
- Pallidal deep brain stimulation for dystonia: a case seriesMelita T Petrossian
Department of Neurology, Brigham and Women s Hospital and
J Neurosurg Pediatr 12:582-7. 2013..However, there are limited data on long-term outcome and treatment complications. The authors report on the short- and long-term effects of pallidal DBS in a cohort of patients with early-onset dystonia...
- Pre-synaptic release deficits in a DYT1 dystonia mouse modelFumiaki Yokoi
Department of Neurology, College of Medicine, University of Florida, Gainesville, Florida, USA
PLoS ONE 8:e72491. 2013....
- Engineering animal models of dystoniaJanneth Oleas
Department of Neurology, College of Medicine, University of Florida, Gainesville, Florida 32610, USA
Mov Disord 28:990-1000. 2013..These results indicate that genetic animal models are powerful tools to elucidate the pathophysiology and to further develop new therapeutics for dystonia...
- Mutations in GNAL cause primary torsion dystoniaTania Fuchs
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA
Nat Genet 45:88-92. 2013..Val137Met in the other. Screening of GNAL in 39 families with PTD identified 6 additional new mutations in this gene. Impaired function of several of the mutants was shown by bioluminescence resonance energy transfer (BRET) assays...
- Evaluation of TorsinA as a target for Parkinson disease therapy in mouse modelsXinru Li
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America
PLoS ONE 7:e50063. 2012..Nevertheless, these data do seem to support the view that torsinA is unlikely to be successfully translated as a target of therapy for human PD...
- Neurogenesis and neuronal migration in the forebrain of the TorsinA knockout mouse embryoDeirdre M McCarthy
Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32303, USA
Dev Neurosci 34:366-78. 2012..These subtle developmental changes are consistent with a lack of significant changes in neuronal numbers, neuronal positioning or size of brain regions in DYT1 dystonia patients...
- Cholinergic dysfunction alters synaptic integration between thalamostriatal and corticostriatal inputs in DYT1 dystoniaGiuseppe Sciamanna
Department of Neuroscience, University Tor Vergata Laboratory of Neurophysiology and Synaptic Plasticity, Fondazione Santa Lucia Istituto di Ricovero e Cura a Carattere Scientifico, 00143 Rome, Italy
J Neurosci 32:11991-2004. 2012....
- Psychiatric disorders in rapid-onset dystonia-parkinsonismAllison Brashear
Department of Neurology, Wake Forest School of Medicine, Wake Forest Baptist Health, Winston Salem, NC, USA
Neurology 79:1168-73. 2012..This study examines psychiatric morbidity for 23 patients with RDP in 10 families with family member control subjects and in 3 unrelated patients with RDP, totaling 56 individuals...
- Genetically engineered microvesicles carrying suicide mRNA/protein inhibit schwannoma tumor growthArda Mizrak
Department of Neurology and Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA
Mol Ther 21:101-8. 2013..Taken together, these studies suggest that MVs can serve as novel cell-derived "liposomes" to effectively deliver therapeutic mRNA/proteins to treatment of diseases...
- Dimerization of the DYT6 dystonia protein, THAP1, requires residues within the coiled-coil domainCem Sengel
Neuroscience Center, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
J Neurochem 118:1087-100. 2011..These observations offer additional insight into the role of the coiled-coil domain in THAP1, which may facilitate future analyses of DYT6 mutations in this region...
- TorsinA participates in endoplasmic reticulum-associated degradationFlavia C Nery
1 Neuroscience Center, Department of Neurology, and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02114, USA 2
Nat Commun 2:393. 2011..Therefore, compromised ERAD function in the cells of DYT1 patients may increase sensitivity to endoplasmic reticulum stress with consequent alterations in neuronal function contributing to the disease state...
- Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia: role of endogenous acetylcholineGiuseppina Martella
Department of Neuroscience, University Tor Vergata, 00133 Rome, Italy
Brain 132:2336-49. 2009..More importantly, our results indicate that an unbalanced cholinergic transmission plays a pivotal role in these alterations, providing a clue to understand the ability of anticholinergic agents to restore motor deficits in dystonia...
- Impaired striatal D2 receptor function leads to enhanced GABA transmission in a mouse model of DYT1 dystoniaGiuseppe Sciamanna
Department of Neuroscience, University Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
Neurobiol Dis 34:133-45. 2009..Our findings demonstrate a disinhibition of striatal GABAergic synaptic activity, that can be at least partially attributed to a D2 DA receptor dysfunction...
- The pathophysiological basis of dystoniasXandra O Breakefield
Department of Neurology and Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
Nat Rev Neurosci 9:222-34. 2008....
- siRNA knock-down of mutant torsinA restores processing through secretory pathway in DYT1 dystonia cellsJeffrey W Hewett
Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA 02129, USA
Hum Mol Genet 17:1436-45. 2008..The ability of allele-specific siRNA for torsinADeltaE to normalize secretory function in DYT1 patient cells supports its potential role as a therapeutic agent in early onset torsion dystonia...
- Phenotypic spectrum and sex effects in eleven myoclonus-dystonia families with epsilon-sarcoglycan mutationsDeborah Raymond
The Alan and Barbara Mirken Department of Neurology, Beth Israel Medical Center, New York, New York 10003, USA
Mov Disord 23:588-92. 2008..0097). We found no association between mutation type and phenotype...
- Dopamine release is impaired in a mouse model of DYT1 dystoniaAygul Balcioglu
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA
J Neurochem 102:783-8. 2007..The defect in DA release as observed may contribute to the abnormalities in motor learning as previously documented in this transgenic mouse model, and may contribute to the clinical symptoms of the human disorder...
- Intragenic Cis and Trans modification of genetic susceptibility in DYT1 torsion dystoniaNeil J Risch
Institute for Human Genetics, University of California at San Francisco, San Francisco, CA 94143, USA
Am J Hum Genet 80:1188-93. 2007..Our findings establish, for the first time, a clinically relevant gene modifier of DYT1...
- Mutant torsinA interferes with protein processing through the secretory pathway in DYT1 dystonia cellsJeffrey W Hewett
Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA 02114, USA
Proc Natl Acad Sci U S A 104:7271-6. 2007..These studies demonstrate the exquisite sensitivity of this reporter system for quantitation of processing through the secretory pathway and support a role for torsinA as an ER chaperone protein...
- Altered responses to dopaminergic D2 receptor activation and N-type calcium currents in striatal cholinergic interneurons in a mouse model of DYT1 dystoniaA Pisani
Clinica Neurologica, Dipartimento di Neuroscienze, Universita Tor Vergata, Rome, Italy, and Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA
Neurobiol Dis 24:318-25. 2006..Our data support the existence of an imbalance between striatal dopaminergic and cholinergic signaling in DYT1 dystonia...
- Effects of genetic variations in the dystonia protein torsinA: identification of polymorphism at residue 216 as protein modifierNorman Kock
Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
Hum Mol Genet 15:1355-64. 2006..They also suggest possible connections between the allelic polymorphism at residue 216 and the penetrance of DYT1 dystonia, as well as a possible role for this polymorphism in related disease states...
- Dystonia-causing mutant torsinA inhibits cell adhesion and neurite extension through interference with cytoskeletal dynamicsJeffrey W Hewett
Molecular Neurogenetics Unit, Departments of Neurology and Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA 02114, USA
Neurobiol Dis 22:98-111. 2006....
- Chemical enhancement of torsinA function in cell and animal models of torsion dystoniaSongsong Cao
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA
Dis Model Mech 3:386-96. 2010....
- Dopamine D2 receptor dysfunction is rescued by adenosine A2A receptor antagonism in a model of DYT1 dystoniaFrancesco Napolitano
CEINGE Biotecnologie Avanzate, Naples, Italy
Neurobiol Dis 38:434-45. 2010....
- The early-onset torsion dystonia-associated protein, torsinA, is a homeostatic regulator of endoplasmic reticulum stress responsePan Chen
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA
Hum Mol Genet 19:3502-15. 2010....
- Milestones in dystoniaLaurie J Ozelius
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA
Mov Disord 26:1106-26. 2011..The challenge ahead includes continued advancement into understanding dystonia's many underlying causes and associated pathology and using this knowledge to advance treatment including preventing genetic disease expression...
- Altered dendritic morphology of Purkinje cells in Dyt1 ΔGAG knock-in and purkinje cell-specific Dyt1 conditional knockout miceLin Zhang
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
PLoS ONE 6:e18357. 2011..Although structural and functional alterations in the cerebellum have been reported in DYT1 dystonia, neuronal morphology has not been examined in vivo...
- Update on the pathology of dystoniaDavid G Standaert
Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, AL 35294, USA
Neurobiol Dis 42:148-51. 2011..Overall the number of well-documented pathological cases available for study is few, and there is an urgent need for additional postmortem studies. This article is part of a Special Issue entitled "Advances in dystonia"...
- Genetic and clinical features of primary torsion dystoniaLaurie J Ozelius
Departments of Genetics and Genomic Sciences and Neurology, Mount Sinai School of Medicine, One Gustave L Levy Pl, Box 1498 New York, NY 10029, USA
Neurobiol Dis 42:127-35. 2011..In this review we will describe the phenotypes associated with these loci and discuss the responsible gene. This article is part of a Special Issue entitled "Advances in dystonia"...
- Molecular pathways in dystoniaD Cristopher Bragg
Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA
Neurobiol Dis 42:136-47. 2011..This review focuses on these molecular pathways, highlighting potential common themes among these dystonias which may serve as areas for future research. This article is part of a Special Issue entitled "Advances in dystonia"...
- Healing genes in the nervous systemXandra O Breakefield
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Neuron 68:178-81. 2010....
- Direct interaction between causative genes of DYT1 and DYT6 primary dystoniaSophie Gavarini
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA
Ann Neurol 68:549-53. 2010..Our findings provide the first evidence that causative genes for primary dystonia intersect in a common pathway and raise the possibility of developing novel therapies targeting this pathway...
- Characterization of Atp1a3 mutant mice as a model of rapid-onset dystonia with parkinsonismMark P DeAndrade
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Behav Brain Res 216:659-65. 2011..These results suggest that the Atp1a3 mutant mouse models several characteristics of RDP and further analysis of this mouse model will provide great insight into pathogenesis of RDP...
- Genetic evidence for an association of the TOR1A locus with segmental/focal dystoniaNutan Sharma
Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA
Mov Disord 25:2183-7. 2010..In contrast, we did not find an association of either allele at the D216H SNP (rs1801968) with focal or segmental dystonia in the same cohort...
- Earlier onset of motor deficits in mice with double mutations in Dyt1 and SgceFumiaki Yokoi
Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL 35294 USA
J Biochem 148:459-66. 2010..Examining additional mutations in other dystonia genes may be beneficial to predict the onset in DYT1 mutation carriers...
- RNAi blocks DYT1 mutant torsinA inclusions in neuronsNorman Kock
Departments of Neurology and Radiology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, USA
Neurosci Lett 395:201-5. 2006..Vector-delivered siRNAs have the potential to decrease the adverse effects of this mutant protein in neurons without affecting wild-type protein...
- Synaptic Function: Effects of the Nerve Injury, Repair, and Altered ActivityTimothy C Cope; Fiscal Year: 2013..The Resume and Summary of Discussion above summarizes the final outcome of the group discussion. OVERALL PROGRAM EVALUATION ..
- Mitochondrial Proteins in Parkinson's DiseaseJ Timothy Greenamyre; Fiscal Year: 2013....
- HEALTHY AGING AND SENILE DEMENTIAJohn Morris; Fiscal Year: 2013..Together, these projects and their supporting cores will focus on preclinical DAT in comparison with healthy brain aging and address the issue of detecting preclinical disease. ..
- Alzheimer's Disease Research CenterDouglas R Galasko; Fiscal Year: 2013..It will provide an environment and core resources to enhance research, foster professional and community training, and coordinate interdisciplinary research. ..
- Emory Alzheimer's Disease CenterAllan I Levey; Fiscal Year: 2013..abstract_text> ..
- Injury and Recovery in Developing BrainFlora M Vaccarino; Fiscal Year: 2013..The long-term goal of these studies is to identify new means of therapeutic intervention to decrease the developmental disability and neurobehavioral sequelae of preterm birth. ..
- Spinal Cord Injury, Plasticity and Transplant Mediated RepairJohn D Houle; Fiscal Year: 2013..This Program Project has direct relevance to the design and implementation of future treatment programs for acute and delayed intervention after SCI. ..
- UNMC EPPLEY CANCER CENTER SUPPORT GRANTKenneth H Cowan; Fiscal Year: 2013....