Research Topics

Genomes and Genes


Brain TorsinA and childhood-onset Dystonia


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