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

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 kappa B (NF-kappa B) activation in Neuro2A cells. The inhibition of NF-kappa B stress-mediated activation with SB203580, a p38 MAPK inhibitor, demonstrated a role for MAPK in NF-kappa B 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-alpha. Withaferin A, a known NF-kappa B inhibitor, reduced mortality of Neuro2A cells overexpressing UBQLN2 species. Conclusions: These results suggest that UBQLN2 dysregulation in neurons can drive NF-kappa B 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.