Ubiquilin-2 drives NF-κB activity and cytosolic TDP-43 aggregation in neuronal cells
Open accessAbstract
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.
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Overexpression of ALS-linked UBQLN2 mutants triggers intracellular inclusions and motor defects in vitro and in vivo.
“while also triggering intracellular inclusions [226,227] and motor defects in vitro and in vivo [226].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [227]
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Autophagy and ALS: mechanistic insights and therapeutic implications
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“triggering intracellular inclusions [226,227] and motor defects in vitro and in vivo [226].”
BackgroundBéland, L.-C., Markovinovic, A., Jakovac, H., De Marchi, F., Bilic, E., Mazzini, L., Kriz, J., & Munitic, I. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa124 · Cited by 125 · see citing works
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Self-citation
- Authors
- Picher-Martel, V., Dutta, K., Phaneuf, D., Sobue, G., & Julien, J.-P.
- Affiliations
- Institut Universitaire en Santé Mentale de Québec (CA)
- Nagoya University (JP)
- Corresponding author
- Julien, Jean-Pierre
- Venue
- Molecular Brain
- Published
- 2015-10-31
- Volume
- 8
- Issue
- 1
- Pages
- 71-71
- ISSN
- 1756-6606 (ISSN-L)
- PMC
- PMC4628361
- OpenAlex
- W1944550035
- Cited by
- 65
- References
- 53
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 4 · 2023: 2 · 2022: 7 · 2021: 14 · 2020: 11 · 2019: 10 · 2018: 7 · 2017: 3 · 2016: 2
- FWCI
- 2.82
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Brain (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (MOP119173)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- UBQLN2, NF-κB activation, TDP-43 aggregation, amyotrophic lateral sclerosis, frontotemporal dementia, ER stress response, p38 MAPK, withaferin A, neurodegeneration, protein aggregation, ubiquitin-proteasome system
- MeSH terms
- Autophagy-Related Proteins, NF-KappaB Inhibitor alpha, Amyotrophic Lateral Sclerosis, Animals, Inclusion Bodies, Cytosol, DNA-Binding Proteins, Humans, Neurons, Stress, Physiological, Ubiquitins, Up-Regulation, NF-kappa B, Cell Death, Cell Cycle Proteins, I-kappa B Proteins, MAP Kinase Signaling System, RNA, Small Interfering, Adaptor Proteins, Signal Transducing, Mice, Transcription Factor RelA, Endoplasmic Reticulum Stress, Protein Aggregates
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