• Register
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.


Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.


The ubiquitin ligase F-box/G-domain protein 1 promotes the degradation of the disease-linked protein torsinA through the ubiquitin-proteasome pathway and macroautophagy.

DYT1 dystonia is a dominantly inherited, disabling neurological disorder with low penetrance that is caused by the deletion of a glutamic acid (ΔE) in the protein torsinA. We previously showed that torsinA(wt) is degraded through macroautophagy while torsinA(ΔE) is targeted to the ubiquitin-proteasome pathway (UPP). The different catabolism of torsinA(wt) and (ΔE) potentially modulates torsinA(wt):torsinA(ΔE) stoichiometry. Therefore, gaining a mechanistic understanding on how the protein quality control machinery clears torsinA(ΔE) in neurons may uncover important regulatory steps in disease pathogenesis. Here, we asked whether F-box/G-domain protein 1 (FBG1), a ubiquitin ligase known to degrade neuronal glycoproteins, is implicated in the degradation of torsinA(ΔE) by the UPP. In a first set of studies completed in cultured cells, we show that FBG1 interacts with and influences the steady-state levels of torsinA(wt) and (ΔE). Interestingly, FBG1 achieves this effect promoting the degradation of torsinA not only through the UPP, but also by macroautophagy. To determine the potential clinical significance of these findings, we asked if eliminating expression of Fbg1 triggers a motor phenotype in torsinA(ΔE) knock in (KI) mice, a model of non-manifesting DYT1 mutation carriers. We detected differences in spontaneous locomotion between aged torsinA(ΔE) KI-Fbg1 knock out and control mice. Furthermore, neuronal levels of torsinA were unaltered in Fbg1 null mice, indicating that redundant systems likely compensate in vivo for the absence of this ubiquitin ligase. In summary, our studies support a non-essential role for FBG1 on the degradation of torsinA and uncover a novel link of FBG1 to the autophagy pathway.

Pubmed ID: 22917612


  • Gordon KL
  • Glenn KA
  • Bode N
  • Wen HM
  • Paulson HL
  • Gonzalez-Alegre P



Publication Data

November 8, 2012

Associated Grants

  • Agency: NINDS NIH HHS, Id: F31NS073348
  • Agency: NINDS NIH HHS, Id: K02 NS058450
  • Agency: NINDS NIH HHS, Id: K02NS058450
  • Agency: NIA NIH HHS, Id: R01 AG034228
  • Agency: NIA NIH HHS, Id: R01AG034228

Mesh Terms

  • Animals
  • Autophagy
  • Blotting, Western
  • Disease Models, Animal
  • Dystonia Musculorum Deformans
  • F-Box Proteins
  • Gene Knock-In Techniques
  • Immunoprecipitation
  • Mice
  • Mice, Knockout
  • Microscopy, Confocal
  • Molecular Chaperones
  • Proteasome Endopeptidase Complex
  • Signal Transduction
  • Transfection
  • Ubiquitin