ArticleScientific reports2016
CUL2-mediated clearance of misfolded TDP-43 is paradoxically affected by VHL in oligodendrocytes in ALS.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 35 citations in OpenAlex.
- The role of E3 ubiquitin ligases in selective types of macroautophagy.EMBO reports · 2026Review
- TDP-43: [GU]-ardian of the transcriptome.Molecular neurodegeneration · 2026Review
- Rsp5/NEDD4 and ESCRT regulate TDP-43 toxicity and turnover via an endolysosomal clearance mechanism.The Journal of cell biology · 2026Article
- Review
- Ubiquitin signatures on aggregating proteins in neurodegeneration.Essays in biochemistry · 2025Review
- Downregulation ofBrain communications · 2025Article
- Post-Translational Variants of Major Proteins in Amyotrophic Lateral Sclerosis Provide New Insights into the Pathophysiology of the Disease.International journal of molecular sciences · 2024Review
- Abundant transcriptomic alterations in the human cerebellum of patients with a C9orf72 repeat expansion.Acta neuropathologica · 2024Article
- The pathogenic mechanism of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis.Neural regeneration research · 2024Review
- IκB kinase phosphorylates cytoplasmic TDP-43 and promotes its proteasome degradation.The Journal of cell biology · 2024Article
- Oligodendrocytes in amyotrophic lateral sclerosis and frontotemporal dementia: the new players on stage.Frontiers in molecular neuroscience · 2024Review
- Emerging Trends in the Field of Inflammation and Proteinopathy in ALS/FTD Spectrum Disorder.Biomedicines · 2023Review
- Praja1 RING-finger E3 ubiquitin ligase is a common suppressor of neurodegenerative disease-associated protein aggregation.Neuropathology : official journal of the Japanese Society of Neuropathology · 2022Article
- Molecular Dissection of TDP-43 as a Leading Cause of ALS/FTLD.International journal of molecular sciences · 2022Review
- Transactivation Response DNA-Binding Protein of 43 (TDP-43) and Glial Cell Roles in Neurological Disorders.Cureus · 2022Review
- Article
- Functional implication of ubiquitinating and deubiquitinating mechanisms in TDP-43 proteinopathies.Frontiers in cell and developmental biology · 2022Review
- Contribution of RNA/DNA Binding Protein Dysfunction in Oligodendrocytes in the Pathogenesis of the Amyotrophic Lateral Sclerosis/Frontotemporal Lobar Degeneration Spectrum Diseases.Frontiers in neuroscience · 2021Review
- Praja1 RING-finger E3 ubiquitin ligase suppresses neuronal cytoplasmic TDP-43 aggregate formation.Neuropathology : official journal of the Japanese Society of Neuropathology · 2020Article
- How Degeneration of Cells Surrounding Motoneurons Contributes to Amyotrophic Lateral Sclerosis.Cells · 2020Review
Corrections and comments
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The molecular machinery responsible for cytosolic accumulation of misfolded TDP-43 in amyotrophic lateral sclerosis (ALS) remains elusive. Here we identified a cullin-2 (CUL2) RING complex as a novel ubiquitin ligase for fragmented forms of TDP-43. The von Hippel Lindau protein (VHL), a substrate binding component of the complex, preferentially recognized misfolded TDP-43 at Glu246 in RNA-recognition motif 2. Recombinant full-length TDP-43 was structurally fragile and readily cleaved, suggesting that misfolded TDP-43 is cleared by VHL/CUL2 in a step-wise manner via fragmentation. Surprisingly, excess VHL stabilized and led to inclusion formation of TDP-43, as well as mutant SOD1, at the juxtanuclear protein quality control center. Moreover, TDP-43 knockdown elevated VHL expression in cultured cells, implying an aberrant interaction between VHL and mislocalized TDP-43 in ALS. Finally, cytoplasmic inclusions especially in oligodendrocytes in ALS spinal cords were immunoreactive to both phosphorylated TDP-43 and VHL. Thus, our results suggest that an imbalance in VHL and CUL2 may underlie oligodendrocyte dysfunction in ALS, and highlight CUL2 E3 ligase emerges as a novel therapeutic potential for ALS.
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