Loss of the dystonia-associated protein torsinA selectively disrupts the neuronal nuclear envelope

Neuron. 2005 Dec 22;48(6):923-32. doi: 10.1016/j.neuron.2005.11.010.


An enigmatic feature of many genetic diseases is that mutations in widely expressed genes cause tissue-specific illness. One example is DYT1 dystonia, a neurodevelopmental disease caused by an in-frame deletion (Deltagag) in the gene encoding torsinA. Here we show that neurons from both torsinA null (Tor1a(-/-)) and homozygous disease mutant "knockin" mice (Tor1a(Deltagag/Deltagag)) contain severely abnormal nuclear membranes, although non-neuronal cell types appear normal. These membrane abnormalities develop in postmigratory embryonic neurons and subsequently worsen with further neuronal maturation, a finding evocative of the developmental dependence of DYT1 dystonia. These observations demonstrate that neurons have a unique requirement for nuclear envelope localized torsinA function and suggest that loss of this activity is a key molecular event in the pathogenesis of DYT1 dystonia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / abnormalities*
  • Brain / metabolism*
  • Brain / physiopathology
  • Carrier Proteins / metabolism
  • Cell Differentiation / genetics
  • Cell Movement / genetics
  • Cells, Cultured
  • Disease Models, Animal
  • Dystonia Musculorum Deformans / genetics
  • Dystonia Musculorum Deformans / metabolism*
  • Dystonia Musculorum Deformans / physiopathology
  • Genetic Predisposition to Disease / genetics
  • HSC70 Heat-Shock Proteins / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Microscopy, Electron, Transmission
  • Molecular Chaperones / genetics*
  • Mutation / genetics
  • Neurons / metabolism*
  • Neurons / pathology
  • Neurons / ultrastructure
  • Nuclear Envelope / metabolism*
  • Nuclear Envelope / pathology
  • Nuclear Envelope / ultrastructure


  • Carrier Proteins
  • Dyt1 protein, mouse
  • HSC70 Heat-Shock Proteins
  • HSPA8 protein, human
  • Membrane Proteins
  • Molecular Chaperones
  • TOR1AIP2 protein, human