Disruption of protein processing in the endoplasmic reticulum of DYT1 knock-in mice implicates novel pathways in dystonia pathogenesis

Genevieve Beauvais, Nicole M. Bode, Jaime L. Watson, Hsiang Wen, Kevin A. Glenn, Hiroyuki Kawano, N. Charles Harata, Michelle E. Ehrlich, Pedro Gonzalez-Alegre

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28 Scopus citations


Dystonia type 1 (DYT1) is a dominantly inherited neurological disease caused by mutations inTOR1A, the gene encoding the endoplasmic reticulum (ER)-resident protein torsinA. Previous work mostly completed in cell-based systems suggests that mutant torsinA alters protein processing in the secretory pathway. We hypothesized that inducing ER stress in the mammalian brain in vivo would trigger or exacerbate mutant torsinA-induced dysfunction. To test this hypothesis, we crossed DYT1 knock-in with p58(IPK)-null mice. The ER co-chaperone p58(IPK) interacts with BiP and assists in protein maturation by helping to fold ER cargo. Its deletion increases the cellular sensitivity to ER stress. We found a lower generation of DYT1 knock-in/p58 knock-out mice than expected from this cross, suggesting a developmental interaction that influences viability. However, surviving animals did not exhibit abnormal motor function. Analysis of brain tissue uncovered dysregulation of eiF2α and Akt/mTOR translational control pathways in the DYT1 brain, a finding confirmed in a second rodent model and in human brain. Finally, an unbiased proteomic analysis identified relevant changes in the neuronal protein landscape suggesting abnormal ER protein metabolism and calcium dysregulation. Functional studies confirmed the interaction between the DYT1 genotype and neuronal calcium dynamics. Overall, these findings advance our knowledge on dystonia, linking translational control pathways and calcium physiology to dystonia pathogenesis and identifying potential new pharmacological targets.

Original languageEnglish
Pages (from-to)10245-10256
Number of pages12
JournalJournal of Neuroscience
Issue number40
StatePublished - 5 Oct 2016


  • Dystonia
  • Eif2alpha
  • Endoplasmic reticulum
  • P58
  • Proteomics
  • Torsina


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