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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.
Bragg Laboratory Group Members
William Hendriks, PhDInstructor Neurology
Christine Vaine, PhDInstructor Neurology
David ChinResearch Technician
Kyle ChinResearch Technician
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.
D. Cristopher Bragg, PhD
Associate Director Collaborative Center for XDP
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