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Electron tomographic analysis of dystonia pathogenesis

  • Author(s): Perez, Alexander Joseph
  • et al.
Abstract

The dystonias are a set of movement disorders associated with neural dysfunction. Due to the large variety in etiology, symptoms, and age of onset of the dystonias, relatively little is known about their pathogenesis and treatments are often administered on a trial-and-error basis. A majority of the cases of DYT1 dystonia, a severe early-onset variant of the disease, are caused by the deletion of a single amino acid in torsinA, a AAA+ protein. The mutation causes a redistribution of torsinA to the nuclear envelope where it acts on LAP1, a protein of the nuclear lamina. The torsinA mutation manifests itself physically by causing the formation of nuclear envelope blebs and perinuclear vesicles. Electron tomography, a tool for producing three-dimensional reconstructions of sub-cellular structures, was used to explore the ultrastructure of these physical abnormalities. The evidence suggests that blebs bud from a single nuclear pore, remain temporarily attached to the inner nuclear membrane via a membranous neck, and eventually bud off into the perinuclear space as vesicles. This process was the same in both torsinA and LAP1 knockout cells, indicating that a normal interaction between the two is necessary to prevent vesicle formation. Nuclear pore density was dramatically decreased from expected levels, indicating that pore damage occurs concomitantly with bleb formation. A set of novel structures, named inner bleb structures, were found to be specific to torsinA KO neurons. Taken together, these findings help elucidate the relatively unexplored pathway of dystonia pathogenesis and may lead to more effective and targeted treatments

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