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

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.

Pubmed ID: 16364897

Authors

  • Goodchild RE
  • Kim CE
  • Dauer WT

Journal

Neuron

Publication Data

December 22, 2005

Associated Grants

  • Agency: NICHD NIH HHS, Id: R01 HD045708-01A1

Mesh Terms

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