title: Ubiquilin-2 drives NF-κB activity and cytosolic TDP-43 aggregation in neuronal cells.
abstract: 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.
authors.affiliation: Research Centre of Institut Universitaire en Santé Mentale de Québec, Laval University, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada.|Department of Psychiatry and Neuroscience, Laval University, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada.
authors.forename: Vincent
authors.initials: V
authors.lastname: Picher-Martel
authors.affiliation: Research Centre of Institut Universitaire en Santé Mentale de Québec, Laval University, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada.|Department of Psychiatry and Neuroscience, Laval University, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada.
authors.forename: Kallol
authors.initials: K
authors.lastname: Dutta
authors.affiliation: Research Centre of Institut Universitaire en Santé Mentale de Québec, Laval University, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada.|Department of Psychiatry and Neuroscience, Laval University, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Phaneuf
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
authors.affiliation: Research Centre of Institut Universitaire en Santé Mentale de Québec, Laval University, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada. jean-pierre.julien@fmed.ulaval.ca.|Department of Psychiatry and Neuroscience, Laval University, 2601 Chemin de la Canardière, Québec, QC, G1J 2G3, Canada. jean-pierre.julien@fmed.ulaval.ca.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Julien
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000071183:Autophagy-Related Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016923:Cell Death; D003600:Cytosol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D002479:Inclusion Bodies / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D066329:Protein Aggregates; D034741:RNA, Small Interfering / Q000378:metabolism; D013312:Stress, Physiological; D051996:Transcription Factor RelA / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D066329:Protein Aggregates; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; C405662:UBQLN2 protein, human; D014452:Ubiquitins; D000072000:NF-KappaB Inhibitor alpha