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

TitleUbiquilin-2 drives NF-κB activity and cytosolic TDP-43 aggregation in neuronal cells.
Publication TypeJournal Article
Year of Publication2015
AuteursPicher-Martel, V, Dutta, K, Phaneuf, D, Sobue, G, Julien, J-P
JournalMol Brain
Date Published2015 Oct 31
KeywordsAmyotrophic Lateral Sclerosis, Animals, Cell Cycle Proteins, Cell Death, Cytosol, DNA-Binding Proteins, Endoplasmic Reticulum Stress, Humans, I-kappa B Proteins, Inclusion Bodies, MAP Kinase Signaling System, Mice, Neurons, NF-kappa B, NF-KappaB Inhibitor alpha, Protein Aggregates, RNA, Small Interfering, Stress, Physiological, Transcription Factor RelA, Ubiquitins, Up-Regulation

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.

Alternate JournalMol Brain
PubMed ID26521126
PubMed Central IDPMC4628361
Grant List / / Canadian Institutes of Health Research / Canada