Ubiquilin-2 drives NF-κB activity and cytosolic TDP-43 aggregation in neuronal cells

Mol Brain. 2015 Oct 31;8(1):71. doi: 10.1186/s13041-015-0162-6.


Background: Mutations in the gene encoding Ubiquilin-2 (UBQLN2) are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). UBQLN2 plays a central role in ubiquitin proteasome system (UPS) and UBQLN2 mutants can form cytoplasmic aggregates in vitro and in vivo.

Results: Here, we report that overexpression of WT or mutant UBQLN2 species enhanced nuclear factor κB (NF-κB) activation in Neuro2A cells. The inhibition of NF-κB stress-mediated activation with SB203580, a p38 MAPK inhibitor, demonstrated a role for MAPK in NF-κB activation by UBQLN2 species. Live cell imaging and microscopy showed that UBQLN2 aggregates are dynamic structures that promote cytoplasmic accumulation of TAR DNA-binding protein (TDP-43), a major component of ALS inclusion bodies. Furthermore, up-regulation of UBQLN2 species in neurons caused an ER-stress response and increased their vulnerability to death by toxic mediator TNF-α. Withaferin A, a known NF-κB inhibitor, reduced mortality of Neuro2A cells overexpressing UBQLN2 species.

Conclusions: These results suggest that UBQLN2 dysregulation in neurons can drive NF-κB activation and cytosolic TDP-43 aggregation, supporting the concept of pathway convergence in ALS pathogenesis. These Ubiquilin-2 pathogenic pathways might represent suitable therapeutic targets for future ALS treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Autophagy-Related Proteins
  • Cell Cycle Proteins / metabolism*
  • Cell Death
  • Cytosol / metabolism*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism*
  • Endoplasmic Reticulum Stress
  • Humans
  • I-kappa B Proteins / metabolism
  • Inclusion Bodies / metabolism
  • MAP Kinase Signaling System
  • Mice
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Neurons / metabolism*
  • Protein Aggregates*
  • RNA, Small Interfering / metabolism
  • Stress, Physiological
  • Transcription Factor RelA / metabolism
  • Ubiquitins / metabolism*
  • Up-Regulation


  • Adaptor Proteins, Signal Transducing
  • Autophagy-Related Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Protein Aggregates
  • RNA, Small Interfering
  • Transcription Factor RelA
  • UBQLN2 protein, human
  • Ubiquitins
  • NF-KappaB Inhibitor alpha