ArticleBiochimica et biophysica acta2013
Ubiquilin-2 (UBQLN2) binds with high affinity to the C-terminal region of TDP-43 and modulates TDP-43 levels in H4 cells: characterization of inhibition by nucleic acids and 4-aminoquinolines.
Article in Biochimica et biophysica acta, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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36 citing papers in PubMed, 63 citations in OpenAlex.
- Multiple motor proteins regulate TDP-43 anterograde axonal transport.Acta neuropathologica · 2026Article
- TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models.The FEBS journal · 2026Review
- UBQLN2 in neurodegenerative disease: mechanistic insights and emerging therapeutic potential.Biochemical Society transactions · 2025Review
- The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).Autophagy reports · 2025Review
- Prion-like Spreading of Disease in TDP-43 Proteinopathies.Brain sciences · 2024Review
- Brain-body mechanisms contribute to sexual dimorphism in amyotrophic lateral sclerosis.Nature reviews. Neurology · 2024Review
- Ion Mobility Mass Spectrometry Unveils Global Protein Conformations in Response to Conditions that Promote and Reverse Liquid-Liquid Phase Separation.Journal of the American Chemical Society · 2023Article
- Looking for answers far away from the soma-the (un)known axonal functions of TDP-43, and their contribution to early NMJ disruption in ALS.Molecular neurodegeneration · 2023Review
- Damaged DNA Is an Early Event of Neurodegeneration in Induced Pluripotent Stem Cell-Derived Motoneurons with UBQLN2International journal of molecular sciences · 2022Article
- Autophagy Dysfunction in ALS: from Transport to Protein Degradation.Journal of molecular neuroscience : MN · 2022Review
- Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons.EMBO reports · 2022Article
- Disrupting the Balance of Protein Quality Control Protein UBQLN2 Accelerates Tau Proteinopathy.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2022Article
- ALS-linked mutations impair UBQLN2 stress-induced biomolecular condensate assembly in cells.Journal of neurochemistry · 2021Article
- Review
- Regulation of TDP-43 phosphorylation in aging and disease.GeroScience · 2021Article
- The Different Faces of the TDP-43 Low-Complexity Domain: The Formation of Liquid Droplets and Amyloid Fibrils.International journal of molecular sciences · 2021Review
- The Regulatory Role of RNA Metabolism Regulator TDP-43 in Human Cancer.Frontiers in oncology · 2021Review
- Structure, dynamics and functions of UBQLNs: at the crossroads of protein quality control machinery.The Biochemical journal · 2020Review
- Review
- Stress granules and neurodegeneration.Nature reviews. Neuroscience · 2019Review
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2 authors at 1 institution in 1 country.
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Abstract
Recently, it was reported that mutations in the ubiquitin-like protein ubiquilin-2 (UBQLN2) are associated with X-linked amyotrophic lateral sclerosis (ALS), and that both wild-type and mutant UBQLN2 can co-localize with aggregates of C-terminal fragments of TAR DNA binding protein (TDP-43). Here, we describe a high affinity interaction between UBQLN2 and TDP-43 and demonstrate that overexpression of both UBQLN2 and TDP-43 reduces levels of both exogenous and endogenous TDP-43 in human H4 cells. UBQLN2 bound with high affinity to both full length TDP-43 and a C-terminal TDP-43 fragment (261-414 aa) with KD values of 6.2nM and 8.7nM, respectively. Both DNA oligonucleotides and 4-aminoquinolines, which bind to TDP-43, also inhibited UBQLN2 binding to TDP-43 with similar rank order affinities compared to inhibition of oligonucleotide binding to TDP-43. Inhibitor characterization experiments demonstrated that the DNA oligonucleotides noncompetitively inhibited UBQLN2 binding to TDP-43, which is consistent with UBQLN2 binding to the C-terminal region of TDP-43. Interestingly, the 4-aminoquinolines were competitive inhibitors of UBQLN2 binding to TDP-43, suggesting that these compounds also bind to the C-terminal region of TDP-43. In support of the biochemical data, co-immunoprecipitation experiments demonstrated that both TDP-43 and UBQLN2 interact in human neuroglioma H4 cells. Finally, overexpression of UBQLN2 in the presence of overexpressed full length TDP-43 or C-terminal TDP-43 (170-414) dramatically lowered levels of both full length TDP-43 and C-terminal TDP-43 fragments (CTFs). Consequently, these data suggest that UBQLN2 enhances the clearance of TDP-43 and TDP-43 CTFs and therefore may play a role in the development of TDP-43 associated neurotoxicity.
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