Bragg Laboratory

Bragg Laboratory -- Chemical Neurobiology of Hereditary Dystonia

The laboratory combines gene expression profiling and chemical screening of novel cellular models to understand the pathogenesis of hereditary dystonias.

Overview

Research in the Bragg laboratory is directed towards the identification of pathogenic mechanisms underlying hereditary forms of dystonia and the development of screening tools to seek novel candidates for treating these disorders.  Their approach involves the derivation and characterization of dystonia cell culture models, including primary fibroblasts, lymphoblasts, and induced pluripotent stem cells (iPSCs), which can be used for probing cellular defects and testing candidate therapeutics.  Current projects are focused on studies of DYT1 and DYT6 dystonias, linked to mutations in TOR1A and THAP1, respectively, as well as X-Linked Dystonia-Parkinsonism (XDP), for which the genetic lesion is not yet known.

Group Members

bragg lab group members

Bragg Laboratory Group Members

William Hendriks, PhD
Instructor Neurology

Christine Vaine, PhD
Instructor Neurology

David Chin
Research Technician

Kyle Chin
Research Technician

Research Projects

Induced pluripotent stem cell (iPSC) models of dystonia

Dystonia patient-specific iPSC lines are being generated by reprogramming of fibroblasts collected by the medical team at the Partners Dystonia Clinic, directed by Dr. Nutan Sharma.  The goal of these studies is to differentiate patient and control iPSC lines into specific neuronal subtypes that have been implicated in the pathogenesis of dystonia.  These differentiated neuronal cells then provide model systems for probing neuron-specific defects associated with particular dystonia genotypes.

Biochemistry of the DYT6 dystonia protein, THAP1

THAP1 is a zinc finger DNA binding protein involved in transcriptional regulation.  More than 90 different mutations in THAP1 have been linked to dystonia in diverse patient populations throughout the world.  Our group provided one of the first biochemical comparisons of different DYT6 mutant variants of THAP1, identifying a leucine zipper-type motif within its carboxy terminus that mediates self-oligomerization.  Ongoing studies are characterizing the effects of dystonia mutations within different protein subdomains on (1) protein:protein interactions and (2) transcriptional activity.

Publications

  1. Update on treatments for dystonia, 2014 Bragg DC, Sharma N Curr Neurol Neurosci Rep. 14(6):454.
  2. Dimerization of the DYT6 dystonia protein, THAP1, requires residues within the coiled-coil domain. 2011 Sengel C, Gavarini S, Sharma N, Ozelius LJ, Bragg DC. J Neurochem. 118(6):1087-100.
  3. Molecular pathways in dystonia. 2010 Bragg DC, Armata IA, Nery FC, Breakefield XO, Sharma N. Neurobiol Dis. 2011 42(2):136-47
  4. Phosphorylation of the homer-binding domain of group I metabotropic glutamate receptors by cyclin-dependent kinase 5. 2009 Orlando LR, Ayala R, Kett LR, Curley AA, Duffner J, Bragg DC, Tsai LH, Dunah AW, Young AB. J Neurochem. 2009 110(2):557-69
  5. Dystonia-causing mutant torsinA inhibits cell adhesion and neurite extension through interference with cytoskeletal dynamics. 2006 Hewett JW, Zeng J, Niland BP, Bragg DC, Breakefield XO. Neurobiol Dis. 22(1):98-111.
  6. Impaired motor learning in mice expressing torsinA with the DYT1 dystonia mutation. Sharma N, Baxter MG, Petravicz J, Bragg DC, Schienda A, Standaert DG, Breakefield XO. 2005 J Neurosci. 25(22):5351-5.
  7. Inhibition of N-linked glycosylation prevents inclusion formation by the dystonia-related mutant form of torsinA. 2004 Bragg DC, Kaufman CA, Kock N, Breakefield XO. Mol Cell Neurosci. 2004 27(4):417-26.
  8. Perinuclear biogenesis of mutant torsin-A inclusions in cultured cells infected with tetracycline-regulated herpes simplex virus type 1 amplicon vectors. 2004 Bragg DC, Camp SM, Kaufman CA, Wilbur JD, Boston H, Schuback DE, Hanson PI, Sena-Esteves M, Breakefield XO. Neuroscience. 2004;125(3):651-61.

Contact

Contact Us

D. Cristopher Bragg, PhD

Associate Director Collaborative Center for XDP

CNY 149 13th Street Massachusetts General Hospital Charlestown, MA 02129
  • Phone: 617-643-5754
  • Fax: 617-726-0740
  • Email Us

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