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.

Public Health Relevance

These efforts will provide insights into the genes/proteins and neuronal pathway affected in dystonia which will inform therapeutic efforts, as well as provide cellular assays and behavioral assays in mouse models to evaluate therapeutic agents in preclinical studies. Impetus will be given to research in dystonia at a nationwide level by providing resource access to dystonia mouse models and clinical information/ samples.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
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Special Emphasis Panel (ZNS1-SRB-B (15))
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Sieber, Beth-Anne
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Massachusetts General Hospital
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