Torsion dystonia is one of the most common and least well understood of movement disorders in humans. Affected individuals manifest contracted, twisting postures due to abnormal neurotransmission in the basal ganglia. Early onset torsion dystonia, the most common and severe of the hereditary dystonias, is a dominant disorder with reduced penetrance that manifests during a window of childhood development. Most cases of this disease are caused by inframe deletions in the DYT1 (TORIA) gene, which encodes a novel AAA+ chaperone protein, torsinA, with three homologous family members. The goals of this Program are to elucidate the location and function of torsinA in the nervous system during development and adult life, and to determine how mutations in torsinA perturb these functions. Our hypothesis is that defects in torsinA interfer with vesicle trafficking causing abnormal release of dopamine in the striatum, and, in turn, to alterations in the modeling of neuronal circuitry in the basal ganglia with subsequent compromise of motor control and learning. One Project will focus on determining whether torsinA is a component of vesicle trafficking and release mechanisms, and how expression of mutant torsinA affects signaling, receptor density and dopamine homeostasis in the striatum of humans and mouse models. A Second Project will investigate the distribution of the torsins in the developing mouse brain and how expression of mutant torsinA affects neuronal migration, process extension and synaptogenesis in targeted regions using transgenic mice and knock-out. A Third Project will explore the role of torsin in development of the nervous system in Drosophila and in protein trafficking in specific neuronal populations, and identify genes which can modify torsin-related functions. A Fourth Project will generate and characterize transgenic and conditional knock-out mice for torsinA with respect to motor control and learning and in response to pharmacologic manipulations of dopamine receptors. These Projects will be supported by an administrative core, and cores for biochemistry and antibody generation and clinical sample collection, databasing and pilot studies. Findings should provide insight into dysfunction of dopaminergic neurons, also involved in Parkinson's disease, and potential therapeutic interventions.
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